Nutraceuticals and their Derived Nano-Formulations for the Prevention
and Treatment of Alzheimer's Disease

Ashif       Iqubal; Mohammad    Kashif    Iqubal; Syed    Abul    Fazal; Faheem    Hyder    Pottoo; Syed    Ehtaishamul    Haque
doi:10.2174/1874467214666210309115605
Abstract

Alzheimer’s disease (AD) is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. The presence of β-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmarks of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence showed the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceuticals suffer from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic- metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to overcome such issues, various nanoformulations of nutraceuticals have been developed, that allow their effective delivery into the brain owing to reduced particle size, increased lipophilicity, increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focusing on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitations and regulatory aspects of nutraceuticals to ensure safety and efficacy. We have further explored various nanoformulations of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitations and for effective delivery into the brain.
Keywords: Nutraceuticals, nanoformulation, blood-brain barrier, neuroinflammation, tau proteins, dementia, clinical trials.
Graphical Abstract

[1] 
Busche, M.A.; Hyman, B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci.,  2020, 23(10), 1183-1193.
[http://dx.doi.org/10.1038/s41593-020-0687-6] [PMID: 32778792] 
[2] 
Agrawal, I.; Jha, S. Mitochondrial dysfunction and Alzheimer’s disease: Role of microglia. Front. Aging Neurosci.,  2020, 12, 252.
[http://dx.doi.org/10.3389/fnagi.2020.00252] [PMID: 32973488] 
[3] 
Mir, R.H.; Sawhney, G.; Pottoo, F.H.; Mohi-Ud-Din, R.; Madishetti, S.; Jachak, S.M.; Ahmed, Z.; Masoodi, M.H. Role of environmental pollutants in Alzheimer’s disease: a review. Environ. Sci. Pollut. Res. Int.,  2020, 27(36), 44724-44742.
[http://dx.doi.org/10.1007/s11356-020-09964-x] [PMID: 32715424] 
[4] 
Iqubal, A.; Syed, M.A.; Najmi, A.K.; Azam, F.; Barreto, G.E.; Iqubal, M.K.; Ali, J.; Haque, S.E. Nano-engineered nerolidol loaded lipid carrier delivery system attenuates cyclophosphamide neurotoxicity - Probable role of NLRP3 inflammasome and caspase-1. Exp. Neurol.,  2020, 334, 113464.
[http://dx.doi.org/10.1016/j.expneurol.2020.113464] [PMID: 32941795] 
[5] 
Iqubal, A.; Sharma, S.; Sharma, K.; Bhavsar, A.; Hussain, I.; Iqubal, M.K.; Kumar, R. Intranasally administered pitavastatin ameliorates pentylenetetrazol-induced neuroinflammation, oxidative stress and cognitive dysfunction. Life Sci.,  2018, 211, 172-181.
[http://dx.doi.org/10.1016/j.lfs.2018.09.025] [PMID: 30227132] 
[6] 
Gottesman, R.T.; Stern, Y. Behavioral and psychiatric symptoms of dementia and rate of decline in Alzheimer’s disease. Front. Pharmacol.,  2019, 10, 1062.
[http://dx.doi.org/10.3389/fphar.2019.01062] [PMID: 31616296] 
[7] 
Iqubal, A.; Ahmed, M.; Ahmad, S.; Sahoo, C.R.; Iqubal, M.K.; Haque, S.E. Environmental neurotoxic pollutants: review. Environ. Sci. Pollut. Res. Int.,  2020, 27(33), 41175-41198.
[http://dx.doi.org/10.1007/s11356-020-10539-z] [PMID: 32820440] 
[8] 
Mushtaq, U.; Shafi, A.; Khanday, F.A. Current challenges in Alzheimer’s disease. Front. Clin. Drug Res. Dement.,  2020, 1, 187.
[http://dx.doi.org/10.2174/9789811410949120010008] 
[9] 
Langa, K.M.; Burke, J.F. Preclinical Alzheimer disease—early diagnosis or overdiagnosis? JAMA Intern. Med.,  2019, 179(9), 1161-1162.
[http://dx.doi.org/10.1001/jamainternmed.2019.2629] [PMID: 31282928] 
[10] 
Uddin, M.S.; Kabir, M.T.; Tewari, D.; Mamun, A.A.; Mathew, B.; Aleya, L.; Barreto, G.E.; Bin-Jumah, M.N.; Abdel-Daim, M.M.; Ashraf, G.M. Revisiting the role of brain and peripheral Aβ in the pathogenesis of Alzheimer’s disease. J. Neurol. Sci.,  2020, 416, 116974.
[http://dx.doi.org/10.1016/j.jns.2020.116974] [PMID: 32559516] 
[11] 
Zhang, T.; Chen, D.; Lee, T.H. Phosphorylation Signaling in APP Processing in Alzheimer’s Disease. Int. J. Mol. Sci.,  2019, 21(1), 209.
[http://dx.doi.org/10.3390/ijms21010209] [PMID: 31892243] 
[12] 
Uddin, M.S.; Kabir, M.T.; Rahman, M.S.; Behl, T.; Jeandet, P.; Ashraf, G.M.; Najda, A.; Bin-Jumah, M.N.; El-Seedi, H.R.; Abdel-Daim, M.M. Revisiting the amyloid cascade hypothesis: from anti-Aβ therapeutics to auspicious new ways for Alzheimer’s disease. Int. J. Mol. Sci.,  2020, 21(16), 5858.
[http://dx.doi.org/10.3390/ijms21165858] [PMID: 32824102] 
[13] 
Balducci, C.; Forloni, G. Doxycycline for Alzheimer’s disease: fighting β-amyloid oligomers and neuroinflammation. Front. Pharmacol.,  2019, 10, 738.
[http://dx.doi.org/10.3389/fphar.2019.00738] [PMID: 31333460] 
[14] 
Goswami, S.; Kareem, O.; Goyal, R.K.; Mumtaz, S.M.; Tonk, R.K.; Gupta, R.; Pottoo, F.H. Role of Forkhead Transcription Factors of the O Class (FoxO) in Development and Progression of Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets,  2020, 19(9), 709-721.
[http://dx.doi.org/10.2174/1871527319666201001105553] [PMID: 33001019] 
[15] 
Li, S.; Selkoe, D.J. A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain. J. Neurochem.,  2020, 154(6), 583-597.
[http://dx.doi.org/10.1111/jnc.15007] [PMID: 32180217] 
[16] 
Ibrahim, A.M.; Pottoo, F.H.; Dahiya, E.S.; Khan, F.A.; Kumar, J.B.S. Neuron-glia interactions: Molecular basis of Alzheimer’s disease and applications of neuroproteomics. Eur. J. Neurosci.,  2020, 52(2), 2931-2943.
[http://dx.doi.org/10.1111/ejn.14838] [PMID: 32463535] 
[17] 
Dá Mesquita, S.; Ferreira, A.C.; Sousa, J.C.; Correia-Neves, M.; Sousa, N.; Marques, F. Insights on the pathophysiology of Alzheimer’s disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci. Biobehav. Rev.,  2016, 68, 547-562.
[http://dx.doi.org/10.1016/j.neubiorev.2016.06.014] [PMID: 27328788] 
[18] 
Wang, Y.; Shi, Y.; Wei, H. Calcium dysregulation in Alzheimer’s disease: A target for new drug development. J. Alzheimers Dis. Parkinsonism,  2017, 7(5), 374.
[http://dx.doi.org/10.4172/2161-0460.1000374] [PMID: 29214114] 
[19] 
Kamat, P.K.; Kalani, A.; Rai, S.; Swarnkar, S.; Tota, S.; Nath, C.; Tyagi, N. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol. Neurobiol.,  2016, 53(1), 648-661.
[http://dx.doi.org/10.1007/s12035-014-9053-6] [PMID: 25511446] 
[20] 
Sharma, P.; Sharma, A.; Fayaz, F.; Wakode, S.; Pottoo, F.H. Biological Signatures of Alzheimer’s Disease. Curr. Top. Med. Chem.,  2020, 20(9), 770-781.
[http://dx.doi.org/10.2174/1568026620666200228095553] [PMID: 32108008] 
[21] 
Nordberg, A.; Svensson, A-L. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Saf.,  1998, 19(6), 465-480.
[http://dx.doi.org/10.2165/00002018-199819060-00004] [PMID: 9880090] 
[22] 
Kabir, M.T.; Sufian, M.A.; Uddin, M.S.; Begum, M.M.; Akhter, S.; Islam, A.; Mathew, B.; Islam, M.S.; Amran, M.S.; Md Ashraf, G. NMDA receptor antagonists: Repositioning of memantine as a multitargeting agent for Alzheimer’s therapy. Curr. Pharm. Des.,  2019, 25(33), 3506-3518.
[http://dx.doi.org/10.2174/1381612825666191011102444] [PMID: 31604413] 
[23] 
Sawikr, Y.; Yarla, N.S.; Peluso, I.; Kamal, M.A.; Aliev, G.; Bishayee, A. Neuroinflammation in Alzheimer’s disease: the preventive and therapeutic potential of polyphenolic nutraceuticals. In: Advances in protein chemistry and structural biology; Elsevier, 2017; Vol. 108, pp. 33-57.
[24] 
Babazadeh, A.; Mohammadi Vahed, F.; Jafari, S.M. Nanocarrier- mediated brain delivery of bioactives for treatment/prevention of neurodegenerative diseases. J. Control. Release,  2020, 321, 211-221.
[http://dx.doi.org/10.1016/j.jconrel.2020.02.015] [PMID: 32035189] 
[25] 
Rehman, S.; Nabi, B.; Pottoo, F.H.; Baboota, S.; Ali, J. Lipid nanoformulations in the treatment of neuropsychiatric diseases: An approach to overcome the blood brain barrier. Curr. Drug Metab.,  2020, 21(9), 674-684.
[http://dx.doi.org/10.2174/1573399816666200627214129] [PMID: 32593280] 
[26] 
Kakkar, V.; Kumari, P.; Adlakha, S.; Kaur, I.P. Curcumin and Its Nanoformulations as Therapeutic for Alzheimer’s Disease In: Nanobiotechnology in Neurodegenerative Diseases; Springer, 2019; pp. 343-367.
[http://dx.doi.org/10.1007/978-3-030-30930-5_14] 
[27] 
Uddin, M.S.; Kabir, M.T. Oxidative stress in Alzheimer’s disease: molecular hallmarks of underlying vulnerability. In: Biological, Diagnostic and Therapeutic Advances in Alzheimer’s Disease; Springer, 2019; pp. 91-115.
[http://dx.doi.org/10.1007/978-981-13-9636-6_5] 
[28] 
Iqubal, A.; Sharma, S.; Najmi, A.K.; Syed, M.A.; Ali, J.; Alam, M.M.; Haque, S.E. Nerolidol ameliorates cyclophosphamide-induced oxidative stress, neuroinflammation and cognitive dysfunction: Plausible role of Nrf2 and NF- κB. Life Sci.,  2019, 236, 116867.
[http://dx.doi.org/10.1016/j.lfs.2019.116867] [PMID: 31520598] 
[29] 
Perez Ortiz, J.M.; Swerdlow, R.H. Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br. J. Pharmacol.,  2019, 176(18), 3489-3507.
[http://dx.doi.org/10.1111/bph.14585] [PMID: 30675901] 
[30] 
Weidling, I.; Swerdlow, R.H. Mitochondrial dysfunction and stress responses in alzheimer’s disease. Biology (Basel),  2019, 8(2), 39.
[http://dx.doi.org/10.3390/biology8020039] [PMID: 31083585] 
[31] 
Iqubal, A.; Sharma, S.; Ansari, M.A.; Najmi, A.K.; Syed, M.A.; Ali, J.; Alam, M.M.; Ahmad, S.; Haque, S.E. Nerolidol attenuates cyclophosphamide-induced cardiac inflammation, apoptosis and fibrosis in Swiss Albino mice. Eur. J. Pharmacol.,  2019, 863, 172666.
[http://dx.doi.org/10.1016/j.ejphar.2019.172666] [PMID: 31541628] 
[32] 
Yan, M.H.; Wang, X.; Zhu, X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med.,  2013, 62, 90-101.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.11.014] [PMID: 23200807] 
[33] 
Sultana, R.; Perluigi, M.; Butterfield, D.A. Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. Free Radic. Biol. Med.,  2013, 62, 157-169.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.09.027] [PMID: 23044265] 
[34] 
Tyagi, E.; Agrawal, R.; Nath, C.; Shukla, R. Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain. J. Neuroimmunol.,  2008, 205(1-2), 51-56.
[http://dx.doi.org/10.1016/j.jneuroim.2008.08.015] [PMID: 18838174] 
[35] 
Multhaup, G.; Ruppert, T.; Schlicksupp, A.; Hesse, L.; Beher, D.; Masters, C.L.; Beyreuther, K. Reactive oxygen species and Alzheimer’s disease. Biochem. Pharmacol.,  1997, 54(5), 533-539.
[http://dx.doi.org/10.1016/S0006-2952(97)00062-2] [PMID: 9337068] 
[36] 
Manoharan, S.; Guillemin, G.J.; Abiramasundari, R.S.; Essa, M.M.; Akbar, M.; Akbar, M.D. The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: a mini review. Oxid. Med. Cell. Longev.,  2016, 2016, 8590578.
[37] 
Qin, L.; Liu, Y.; Cooper, C.; Liu, B.; Wilson, B.; Hong, J.S. Microglia enhance β-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J. Neurochem.,  2002, 83(4), 973-983.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01210.x] [PMID: 12421370] 
[38] 
Mamun, A.A.; Uddin, M.S.; Mathew, B.; Ashraf, G.M. Toxic tau: structural origins of tau aggregation in Alzheimer’s disease. Neural Regen. Res.,  2020, 15(8), 1417-1420.
[http://dx.doi.org/10.4103/1673-5374.274329] [PMID: 31997800] 
[39] 
Avila, J. Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett.,  2006, 580(12), 2922-2927.
[http://dx.doi.org/10.1016/j.febslet.2006.02.067] [PMID: 16529745] 
[40] 
Takeda, S. Progression of Alzheimer’s disease, tau propagation, and its modifiable risk factors. Neurosci. Res.,  2019, 141, 36-42.
[http://dx.doi.org/10.1016/j.neures.2018.08.005] [PMID: 30120962] 
[41] 
Bejanin, A.; Schonhaut, D.R.; La Joie, R.; Kramer, J.H.; Baker, S.L.; Sosa, N.; Ayakta, N.; Cantwell, A.; Janabi, M.; Lauriola, M.; O’Neil, J.P.; Gorno-Tempini, M.L.; Miller, Z.A.; Rosen, H.J.; Miller, B.L.; Jagust, W.J.; Rabinovici, G.D. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain,  2017, 140(12), 3286-3300.
[http://dx.doi.org/10.1093/brain/awx243] [PMID: 29053874] 
[42] 
Oliver, D.M.A.; Reddy, P.H. Molecular basis of Alzheimer’s disease: focus on mitochondria. J. Alzheimers Dis.,  2019, 72(s1), S95-S116.
[http://dx.doi.org/10.3233/JAD-190048] [PMID: 30932888] 
[43] 
Verkhratsky, A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev.,  2005, 85(1), 201-279.
[http://dx.doi.org/10.1152/physrev.00004.2004] [PMID: 15618481] 
[44] 
Benarroch, E.E. Neuronal voltage-gated calcium channels: brief overview of their function and clinical implications in neurology. Neurology,  2010, 74(16), 1310-1315.
[http://dx.doi.org/10.1212/WNL.0b013e3181da364b] [PMID: 20404312] 
[45] 
Schampel, A.; Kuerten, S. Danger: high voltage—the role of voltage-gated calcium channels in central nervous system pathology. Cells,  2017, 6(4), 43.
[http://dx.doi.org/10.3390/cells6040043] [PMID: 29140302] 
[46] 
Iqubal, A.; Iqubal, M.K.; Sharma, S.; Ansari, M.A.; Najmi, A.K.; Ali, S.M.; Ali, J.; Haque, S.E. Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sci.,  2019, 218, 112-131.
[http://dx.doi.org/10.1016/j.lfs.2018.12.018] [PMID: 30552952] 
[47] 
Stutzmann, G.E. Calcium dysregulation, IP3 signaling, and Alzheimer’s disease. Neuroscientist,  2005, 11(2), 110-115.
[http://dx.doi.org/10.1177/1073858404270899] [PMID: 15746379] 
[48] 
Misquitta, C.M.; Mack, D.P.; Grover, A.K. Sarco/endoplasmic reticulum Ca2+ (SERCA)-pumps: link to heart beats and calcium waves. Cell Calcium,  1999, 25(4), 277-290.
[http://dx.doi.org/10.1054/ceca.1999.0032] [PMID: 10456225] 
[49] 
Popugaeva, E.; Pchitskaya, E.; Bezprozvanny, I. Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease - A therapeutic opportunity? Biochem. Biophys. Res. Commun.,  2017, 483(4), 998-1004.
[http://dx.doi.org/10.1016/j.bbrc.2016.09.053] [PMID: 27641664] 
[50] 
Itkin, A.; Dupres, V.; Dufrêne, Y.F.; Bechinger, B.; Ruysschaert, J-M.; Raussens, V. Calcium ions promote formation of amyloid β-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer’s disease. PLoS One,  2011, 6(3), e18250.
[http://dx.doi.org/10.1371/journal.pone.0018250] [PMID: 21464905] 
[51] 
Ferreiro, E.; Oliveira, C.R.; Pereira, C.M.F. The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway. Neurobiol. Dis.,  2008, 30(3), 331-342.
[http://dx.doi.org/10.1016/j.nbd.2008.02.003] [PMID: 18420416] 
[52] 
Castillo, C.; Martinez, J.C.; Longart, M.; García, L.; Hernández, M.; Carballo, J.; Rojas, H.; Matteo, L.; Casique, L.; Escalona, J.L.; Rodríguez, Y.; Rodriguez, J.; Hernández, D.; Balbi, D.; Villegas, R. Extracellular application of CRMP2 increases cytoplasmic calcium through NMDA receptors. Neuroscience,  2018, 376, 204-223.
[http://dx.doi.org/10.1016/j.neuroscience.2018.02.002] [PMID: 29555037] 
[53] 
Skowrońska, K.; Obara-Michlewska, M.; Zielińska, M.; Albrecht, J. NMDA receptors in astrocytes: In search for roles in neurotransmission and astrocytic homeostasis. Int. J. Mol. Sci.,  2019, 20(2), 309.
[http://dx.doi.org/10.3390/ijms20020309] [PMID: 30646531] 
[54] 
Liu, J.; Wei, L.; Wang, Z.; Song, S.; Lin, Z.; Zhu, J.; Ren, X.; Kong, L. Protective effect of Liraglutide on diabetic retinal neurodegeneration via inhibiting oxidative stress and endoplasmic reticulum stress. Neurochem. Int.,  2020, 133, 104624.
[http://dx.doi.org/10.1016/j.neuint.2019.104624] [PMID: 31794832] 
[55] 
Uddin, M.S.; Tewari, D.; Sharma, G.; Kabir, M.T.; Barreto, G.E.; Bin-Jumah, M.N.; Perveen, A.; Abdel-Daim, M.M.; Ashraf, G.M. Molecular mechanisms of ER stress and UPR in the pathogenesis of Alzheimer’s disease. Mol. Neurobiol.,  2020, 57(7), 2902-2919.
[http://dx.doi.org/10.1007/s12035-020-01929-y] [PMID: 32430843] 
[56] 
Wang, M.; Wey, S.; Zhang, Y.; Ye, R.; Lee, A.S. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid. Redox Signal.,  2009, 11(9), 2307-2316.
[http://dx.doi.org/10.1089/ars.2009.2485] [PMID: 19309259] 
[57] 
Torres, M.; Encina, G.; Soto, C.; Hetz, C. Abnormal calcium homeostasis and protein folding stress at the ER: A common factor in familial and infectious prion disorders. Commun. Integr. Biol.,  2011, 4(3), 258-261.
[http://dx.doi.org/10.4161/cib.4.3.15019] [PMID: 21980554] 
[58] 
Hashimoto, S.; Saido, T.C. Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer’s disease. Open Biol.,  2018, 8(4), 180024.
[http://dx.doi.org/10.1098/rsob.180024] [PMID: 29695619] 
[59] 
Lin, L.; Liu, G.; Yang, L. Crocin improves cognitive behavior in rats with alzheimer's disease by regulating endoplasmic reticulum stress and apoptosis. Biomed Res. Int.,  2019, 2019, 9454913.
[60] 
Gerakis, Y.; Hetz, C. Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease. FEBS J.,  2018, 285(6), 995-1011.
[http://dx.doi.org/10.1111/febs.14332] [PMID: 29148236] 
[61] 
Uddin, M.S.; Kabir, M.T.; Mamun, A.A.; Barreto, G.E.; Rashid, M.; Perveen, A.; Ashraf, G.M. Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease. Int. Immunopharmacol.,  2020, 84, 106479.
[http://dx.doi.org/10.1016/j.intimp.2020.106479] [PMID: 32353686] 
[62] 
Wang, J.; Song, Y.; Chen, Z.; Leng, S. X. Connection between systemic inflammation and neuroinflammation underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases. Oxid. Med. Cell. Longev.,  2018, 2018, 1972714.
[http://dx.doi.org/10.1155/2018/1972714] 
[63] 
Subramaniyan, S.; Terrando, N. Neuroinflammation and Perioperative Neurocognitive Disorders. Anesth. Analg.,  2019, 128(4), 781-788.
[http://dx.doi.org/10.1213/ANE.0000000000004053] [PMID: 30883423] 
[64] 
Zenaro, E.; Piacentino, G.; Constantin, G. The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis.,  2017, 107, 41-56.
[http://dx.doi.org/10.1016/j.nbd.2016.07.007] [PMID: 27425887] 
[65] 
Priller, J.; Prinz, M. Targeting microglia in brain disorders. Science,  2019, 365(6448), 32-33.
[http://dx.doi.org/10.1126/science.aau9100] [PMID: 31273114] 
[66] 
Bohlen, C.J.; Friedman, B.A.; Dejanovic, B.; Sheng, M. Microglia in brain development, homeostasis, and neurodegeneration. Annu. Rev. Genet.,  2019, 53, 263-288.
[http://dx.doi.org/10.1146/annurev-genet-112618-043515] [PMID: 31518519] 
[67] 
Kaur, D.; Sharma, V.; Deshmukh, R. Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease. Inflammopharmacology,  2019, 27(4), 663-677.
[http://dx.doi.org/10.1007/s10787-019-00580-x] [PMID: 30874945] 
[68] 
Siracusa, R.; Fusco, R.; Cuzzocrea, S. Astrocytes: role and functions in brain pathologies. Front. Pharmacol.,  2019, 10, 1114.
[http://dx.doi.org/10.3389/fphar.2019.01114] [PMID: 31611796] 
[69] 
Carter, S.F.; Herholz, K.; Rosa-Neto, P.; Pellerin, L.; Nordberg, A.; Zimmer, E.R. Astrocyte biomarkers in Alzheimer’s disease. Trends Mol. Med.,  2019, 25(2), 77-95.
[http://dx.doi.org/10.1016/j.molmed.2018.11.006] [PMID: 30611668] 
[70] 
Parpura, V.; Verkhratsky, A. Homeostatic function of astrocytes: Ca(2+) and Na(+) signalling. Transl. Neurosci.,  2012, 3(4), 334-344.
[http://dx.doi.org/10.2478/s13380-012-0040-y] [PMID: 23243501] 
[71] 
Bélanger, M.; Allaman, I.; Magistretti, P.J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab.,  2011, 14(6), 724-738.
[http://dx.doi.org/10.1016/j.cmet.2011.08.016] [PMID: 22152301] 
[72] 
Brown, A.M.; Ransom, B.R. Astrocyte glycogen and brain energy metabolism. Glia,  2007, 55(12), 1263-1271.
[http://dx.doi.org/10.1002/glia.20557] [PMID: 17659525] 
[73] 
Verkhratsky, A.; Olabarria, M.; Noristani, H.N.; Yeh, C-Y.; Rodriguez, J.J. Astrocytes in Alzheimer’s disease. Neurotherapeutics,  2010, 7(4), 399-412.
[http://dx.doi.org/10.1016/j.nurt.2010.05.017] [PMID: 20880504] 
[74] 
Ahmad, M.H.; Fatima, M.; Mondal, A.C. Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of Alzheimer’s disease: Rational insights for the therapeutic approaches. J. Clin. Neurosci.,  2019, 59, 6-11.
[http://dx.doi.org/10.1016/j.jocn.2018.10.034] [PMID: 30385170] 
[75] 
Frost, G.R.; Li, Y-M. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol.,  2017, 7(12), 170228.
[http://dx.doi.org/10.1098/rsob.170228] [PMID: 29237809] 
[76] 
Nobili, A.; Latagliata, E.C.; Viscomi, M.T.; Cavallucci, V.; Cutuli, D.; Giacovazzo, G.; Krashia, P.; Rizzo, F.R.; Marino, R.; Federici, M.; De Bartolo, P.; Aversa, D.; Dell’Acqua, M.C.; Cordella, A.; Sancandi, M.; Keller, F.; Petrosini, L.; Puglisi-Allegra, S.; Mercuri, N.B.; Coccurello, R.; Berretta, N.; D’Amelio, M. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat. Commun.,  2017, 8(1), 14727.
[http://dx.doi.org/10.1038/ncomms14727] [PMID: 28367951] 
[77] 
Wang, Q.; Jiang, H.; Wang, L.; Yi, H.; Li, Z.; Liu, R. Vitegnoside Mitigates Neuronal Injury, Mitochondrial Apoptosis, and Inflammation in an Alzheimer’s Disease Cell Model via the p38 MAPK/JNK Pathway. J. Alzheimers Dis.,  2019, 72(1), 199-214.
[http://dx.doi.org/10.3233/JAD-190640] [PMID: 31561371] 
[78] 
Chen, S-Y.; Gao, Y.; Sun, J-Y.; Meng, X-L.; Yang, D.; Fan, L-H.; Xiang, L.; Wang, P. Traditional Chinese Medicine: Role in Reducing β-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer’s Disease. Front. Pharmacol.,  2020, 11, 497.
[http://dx.doi.org/10.3389/fphar.2020.00497] [PMID: 32390843] 
[79] 
Trovato Salinaro, A.; Pennisi, M.; Di Paola, R.; Scuto, M.; Crupi, R.; Cambria, M.T.; Ontario, M.L.; Tomasello, M.; Uva, M.; Maiolino, L.; Calabrese, E.J.; Cuzzocrea, S.; Calabrese, V. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms. Immun. Ageing,  2018, 15(1), 8.
[http://dx.doi.org/10.1186/s12979-017-0108-1] [PMID: 29456585] 
[80] 
Erickson, M.A.; Hartvigson, P.E.; Morofuji, Y.; Owen, J.B.; Butterfield, D.A.; Banks, W.A. Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J. Neuroinflammation,  2012, 9(1), 150.
[http://dx.doi.org/10.1186/1742-2094-9-150] [PMID: 22747709] 
[81] 
Lopez Sanchez, M.I.G.; van Wijngaarden, P.; Trounce, I.A. Amyloid precursor protein-mediated mitochondrial regulation and Alzheimer’s disease. Br. J. Pharmacol.,  2019, 176(18), 3464-3474.
[http://dx.doi.org/10.1111/bph.14554] [PMID: 30471088] 
[82] 
Hampel, H.; Vassar, R.; De Strooper, B.; Hardy, J.; Willem, M.; Singh, N.; Zhou, J.; Yan, R.; Vanmechelen, E.; De Vos, A.; Nisticò, R.; Corbo, M.; Imbimbo, B.P.; Streffer, J.; Voytyuk, I.; Timmers, M.; Tahami Monfared, A.A.; Irizarry, M.; Albala, B.; Koyama, A.; Watanabe, N.; Kimura, T.; Yarenis, L.; Lista, S.; Kramer, L.; Vergallo, A. The β-secretase BACE1 in Alzheimer’s disease. Biol. Psychiatry,  2020, S0006-3223(20)30063-9.
[PMID: 32223911] 
[83] 
Sagare, A.; Deane, R.; Bell, R.D.; Johnson, B.; Hamm, K.; Pendu, R.; Marky, A.; Lenting, P.J.; Wu, Z.; Zarcone, T.; Goate, A.; Mayo, K.; Perlmutter, D.; Coma, M.; Zhong, Z.; Zlokovic, B.V. Clearance of amyloid-β by circulating lipoprotein receptors. Nat. Med.,  2007, 13(9), 1029-1031.
[http://dx.doi.org/10.1038/nm1635] [PMID: 17694066] 
[84] 
Shibata, M.; Yamada, S.; Kumar, S.R.; Calero, M.; Bading, J.; Frangione, B.; Holtzman, D.M.; Miller, C.A.; Strickland, D.K.; Ghiso, J.; Zlokovic, B.V. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest.,  2000, 106(12), 1489-1499.
[http://dx.doi.org/10.1172/JCI10498] [PMID: 11120756] 
[85] 
Owen, J.B.; Sultana, R.; Aluise, C.D.; Erickson, M.A.; Price, T.O.; Bu, G.; Banks, W.A.; Butterfield, D.A. Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain. Free Radic. Biol. Med.,  2010, 49(11), 1798-1803.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.013] [PMID: 20869432] 
[86] 
Butterfield, D.A.; Mattson, M.P. Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer’s disease. Neurobiol. Dis.,  2020, 138, 104795.
[http://dx.doi.org/10.1016/j.nbd.2020.104795] [PMID: 32036033] 
[87] 
Alasmari, F.; Alshammari, M.A.; Alasmari, A.F.; Alanazi, W.A.; Alhazzani, K. Neuroinflammatory cytokines induce amyloid beta neurotoxicity through modulating amyloid precursor protein levels/metabolism. BioMed Res. Int., 2018. Article ID 3087475.
[88] 
Gunther, E.C.; Smith, L.M.; Kostylev, M.A.; Cox, T.O.; Kaufman, A.C.; Lee, S.; Folta-Stogniew, E.; Maynard, G.D.; Um, J.W.; Stagi, M. Rescue of transgenic Alzheimer’s pathophysiology by polymeric cellular prion protein antagonists. Cell Rep.,  2019, 26(1), 145-158. e8.
[89] 
Kumar, S.; Reddy, P.H. A new discovery of MicroRNA-455-3p in Alzheimer’s disease. 2019. J. Alzheimers Dis.,  2019, 72(s1), S117-S130.
[http://dx.doi.org/10.3233/JAD-190583] [PMID: 31524168] 
[90] 
Parkin, E.T.; Watt, N.T.; Hussain, I.; Eckman, E.A.; Eckman, C.B.; Manson, J.C.; Baybutt, H.N.; Turner, A.J.; Hooper, N.M.J.P.N.A.S. Cellular prion protein regulates β-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc. Natl. Acad. Sci. USA,  2007, 104(26), 11062-11067.
[http://dx.doi.org/10.1073/pnas.0609621104] [PMID: 17573534] 
[91] 
Freir, D.B.; Nicoll, A.J.; Klyubin, I.; Panico, S.; Mc Donald, J.M.; Risse, E.; Asante, E.A.; Farrow, M.A.; Sessions, R.B.; Saibil, H.R.; Clarke, A.R.; Rowan, M.J.; Walsh, D.M.; Collinge, J. Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat. Commun.,  2011, 2(1), 336.
[http://dx.doi.org/10.1038/ncomms1341] [PMID: 21654636] 
[92] 
Chung, E.; Ji, Y.; Sun, Y.; Kascsak, R.J.; Kascsak, R.B.; Mehta, P.D.; Strittmatter, S.M.; Wisniewski, T. Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer’s disease model mouse. BMC Neurosci.,  2010, 11(1), 130.
[http://dx.doi.org/10.1186/1471-2202-11-130] [PMID: 20946660] 
[93] 
Alibhai, J.D.; Diack, A.B.; Manson, J.C. Unravelling the glial response in the pathogenesis of Alzheimer’s disease. FASEB J.,  2020, 32 (11), 5766-5777 Ibrahim, A. M.; Pottoo, F. H.; Dahiya, E. S.; Khan, F. A.; Kumar, J. S. J. E. J. o. N., Neuron‐glia interaction: Molecular basis of Alzheimer’s disease and applications of neuroproteomics. Eur. J. Neurosci.,  2020, 52(2), 2931-2943.
[PMID: 32463535] 
[94] 
Wu, J.; Li, L. Autoantibodies in Alzheimer’s disease: potential biomarkers, pathogenic roles, and therapeutic implications. J. Biomed. Res.,  2016, 30(5), 361-372.
[PMID: 27476881] 
[95] 
Rosenmann, H.; Meiner, Z.; Geylis, V.; Abramsky, O.; Steinitz, M. Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer’s disease and healthy subjects. Neurosci. Lett.,  2006, 410(2), 90-93.
[http://dx.doi.org/10.1016/j.neulet.2006.01.072] [PMID: 17095156] 
[96] 
Elkon, K.B.; Silverman, G.J. Naturally occurring autoantibodies to apoptotic cells. In: Naturally Occurring Antibodies (NAbs); Springer, 2012; pp. 14-26.
[http://dx.doi.org/10.1007/978-1-4614-3461-0_2] 
[97] 
Nagele, E.; Han, M.; Demarshall, C.; Belinka, B.; Nagele, R. Diagnosis of Alzheimer’s disease based on disease-specific autoantibody profiles in human sera. PLoS One,  2011, 6(8), e23112.
[http://dx.doi.org/10.1371/journal.pone.0023112] [PMID: 21826230] 
[98] 
Acharya, N.K.; Nagele, E.P.; Han, M.; Coretti, N.J.; DeMarshall, C.; Kosciuk, M.C.; Boulos, P.A.; Nagele, R.G. Neuronal PAD4 expression and protein citrullination: possible role in production of autoantibodies associated with neurodegenerative disease. J. Autoimmun.,  2012, 38(4), 369-380.
[http://dx.doi.org/10.1016/j.jaut.2012.03.004] [PMID: 22560840] 
[99] 
Gustaw, K.A.; Garrett, M.R.; Lee, H.G.; Castellani, R.J.; Zagorski, M.G.; Prakasam, A.; Siedlak, S.L.; Zhu, X.; Perry, G.; Petersen, R.B.; Friedland, R.P.; Smith, M.A. Antigen-antibody dissociation in Alzheimer disease: a novel approach to diagnosis. J. Neurochem.,  2008, 106(3), 1350-1356.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05477.x] [PMID: 18485104] 
[100] 
Berry, A.; Vacirca, D.; Capoccia, S.; Bellisario, V.; Malorni, W.; Ortona, E.; Cirulli, F. Anti-ATP synthase autoantibodies induce neuronal death by apoptosis and impair cognitive performance in C57BL/6J mice. J. Alzheimers Dis.,  2013, 33(2), 317-321.
[http://dx.doi.org/10.3233/JAD-2012-121312] [PMID: 22954670] 
[101] 
Nicoll, J.A.; Wilkinson, D.; Holmes, C.; Steart, P.; Markham, H.; Weller, R.O. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med.,  2003, 9(4), 448-452.
[http://dx.doi.org/10.1038/nm840] [PMID: 12640446] 
[102] 
Rinne, J.O.; Brooks, D.J.; Rossor, M.N.; Fox, N.C.; Bullock, R.; Klunk, W.E.; Mathis, C.A.; Blennow, K.; Barakos, J.; Okello, A.A.; Rodriguez Martinez de Liano, S.; Liu, E.; Koller, M.; Gregg, K.M.; Schenk, D.; Black, R.; Grundman, M. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol.,  2010, 9(4), 363-372.
[http://dx.doi.org/10.1016/S1474-4422(10)70043-0] [PMID: 20189881] 
[103] 
Kou, J.; Yang, J.; Lim, J-E.; Pattanayak, A.; Song, M.; Planque, S.; Paul, S.; Fukuchi, K. Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer’s disease: prophylactic and therapeutic applications. Mol. Neurobiol.,  2015, 51(1), 43-56.
[http://dx.doi.org/10.1007/s12035-014-8691-z] [PMID: 24733587] 
[104] 
Ratner, M. Biogen’s early Alzheimer’s data raise hopes, some eyebrows. Nat. Biotechnol.,  2015, 33(5), 438.
[105] 
Boutajangout, A.; Ingadottir, J.; Davies, P.; Sigurdsson, E.M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem.,  2011, 118(4), 658-667.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07337.x] [PMID: 21644996] 
[106] 
Anand, A.; Patience, A.A.; Sharma, N.; Khurana, N. The present and future of pharmacotherapy of Alzheimer’s disease: A comprehensive review. Eur. J. Pharmacol.,  2017, 815, 364-375.
[http://dx.doi.org/10.1016/j.ejphar.2017.09.043] [PMID: 28978455] 
[107] 
Kelly, C.A.; Harvey, R.J.; Cayton, H. Drug treatments for Alzheimer’s disease: Raise clinical and ethical problems.British Medical Journal Publishing Group, 1997. 
[108] 
Josmi, P.; Divya, P.; Rosemol, J. Role of nutraceuticals in Alzheimer’s disease. Pharm. Innovat. J.,  2019, 8(4), 1129-1132.
[109] 
Calfio, C.; Gonzalez, A.; Singh, S. K.; Rojo, L. E.; Maccioni, R. B. The emerging role of nutraceuticals and phytochemicals in the prevention and treatment of Alzheimer’s disease. J. Alzheimers Dis.,  2020, 77(1), 33-51.
[110] 
Makkar, R.; Behl, T.; Bungau, S.; Zengin, G.; Mehta, V.; Kumar, A.; Uddin, M.S.; Ashraf, G.M.; Abdel-Daim, M.M.; Arora, S.; Oancea, R. Nutraceuticals in neurological disorders. Int. J. Mol. Sci.,  2020, 21(12), 4424.
[http://dx.doi.org/10.3390/ijms21124424] [PMID: 32580329] 
[111] 
Prakash, V.; van Boekel, M.A. Nutraceuticals: possible future ingredients and food safety aspects. In: Ensuring Global Food Safety; Elsevier, 2010; pp. 333-338.
[http://dx.doi.org/10.1016/B978-0-12-374845-4.00019-9] 
[112] 
Chauhan, N.B.; Mehla, J. Ameliorative Effects of Nutraceuticals in Neurological Disorders. In: Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease; Elsevier, 2015; pp. 245-260.
[http://dx.doi.org/10.1016/B978-0-12-411462-3.00027-8] 
[113] 
Mir, R.H.; Shah, A.J.; Mohi-Ud-Din, R.; Pottoo, F.H.; Dar, M.A.; Jachak, S.M.; Masoodi, M.H. Natural anti-inflammatory compounds as drug candidates in Alzheimer’s disease. Curr. Med. Chem.,  2021, 28(23), 4799-4825.
[http://dx.doi.org/10.2174/0929867327666200730213215] [PMID: 32744957] 
[114] 
Iqubal, A.; Syed, M.A.; Najmi, A.K.; Ali, J.; Haque, S.E. Ameliorative effect of nerolidol on cyclophosphamide-induced gonadal toxicity in Swiss Albino mice: Biochemical-, histological- and immunohistochemical-based evidences. Andrologia,  2020, 52(4), e13535.
[http://dx.doi.org/10.1111/and.13535] [PMID: 32048763] 
[115] 
Iqubal, A.; Syed, M.A.; Haque, M.M.; Najmi, A.K.; Ali, J.; Haque, S.E. Effect of nerolidol on cyclophosphamide-induced bone marrow and hematologic toxicity in Swiss albino mice. Exp. Hematol.,  2020, 82, 24-32.
[http://dx.doi.org/10.1016/j.exphem.2020.01.007] [PMID: 31987924] 
[116] 
Daliu, P.; Santini, A.; Novellino, E. From pharmaceuticals to nutraceuticals: bridging disease prevention and management. Expert Rev. Clin. Pharmacol.,  2019, 12(1), 1-7.
[http://dx.doi.org/10.1080/17512433.2019.1552135] [PMID: 30484336] 
[117] 
Chiu, H-F.; Venkatakrishnan, K.; Wang, C-K. The role of nutraceuticals as a complementary therapy against various neurodegenerative diseases: A mini-review. J. Tradit. Complement. Med.,  2020, 10(5), 434-439.
[http://dx.doi.org/10.1016/j.jtcme.2020.03.008] [PMID: 32953558] 
[118] 
Sadhukhan, P.; Saha, S.; Dutta, S.; Mahalanobish, S.; Sil, P.C. Nutraceuticals: An emerging therapeutic approach against the pathogenesis of Alzheimer’s disease. Pharmacol. Res.,  2018, 129, 100-114.
[http://dx.doi.org/10.1016/j.phrs.2017.11.028] [PMID: 29183770] 
[119] 
Khare, E.; Fatima, Z. Recent advances and current perspectives in treatment of Alzheimer’s disease. Environ. Conserv. J.,  2020, 21(1&2), 183-186.
[http://dx.doi.org/10.36953/ECJ.2020.211224] 
[120] 
Sabbagh, M.N. Alzheimer’s Disease Drug Development PipelineSpringer, 2020. 
[121] 
Iqubal, A.; Iqubal, M.K.; Khan, A.; Ali, J.; Baboota, S.; Haque, S.E. Gene therapy, a novel therapeutic tool for neurological disorders: Current progress, challenges and future prospective. Curr. Gene Ther.,  2020, 20(3), 184-194.
[http://dx.doi.org/10.2174/1566523220999200716111502] [PMID: 32674730] 
[122] 
Williams, R.J.; Mohanakumar, K.P.; Beart, P.M. Neuro-nutraceuticals: the path to brain health via nourishment is not so distant.Elsevier, 2015. 
[123] 
Dadhania, V.P.; Trivedi, P.P.; Vikram, A.; Tripathi, D.N. Nutraceuticals against Neurodegeneration: A Mechanistic Insight. Curr. Neuropharmacol.,  2016, 14(6), 627-640.
[http://dx.doi.org/10.2174/1570159X14666160104142223] [PMID: 26725888] 
[124] 
Brewer, G.J.; Torricelli, J.R.; Lindsey, A.L.; Kunz, E.Z.; Neuman, A.; Fisher, D.R.; Joseph, J.A. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract. J. Nutr. Biochem.,  2010, 21(10), 991-998.
[http://dx.doi.org/10.1016/j.jnutbio.2009.08.005] [PMID: 19954954] 
[125] 
Shukitt-Hale, B.; Lau, F.C.; Carey, A.N.; Galli, R.L.; Spangler, E.L.; Ingram, D.K.; Joseph, J.A. Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus. Nutr. Neurosci.,  2008, 11(4), 172-182.
[http://dx.doi.org/10.1179/147683008X301487] [PMID: 18681986] 
[126] 
Peng, Q.; Buz’Zard, A.R.; Lau, B.H. Neuroprotective effect of garlic compounds in amyloid-β peptide-induced apoptosis in vitro. Med. Sci. Monit.,  2002, 8(8), BR328-BR337.
[PMID: 12165737] 
[127] 
Okello, E.J.; Mather, J. Comparative kinetics of acetyl- and butyryl-cholinesterase inhibition by green tea catechins|relevance to the symptomatic treatment of Alzheimer’s disease. Nutrients,  2020, 12(4), 1090.
[http://dx.doi.org/10.3390/nu12041090] [PMID: 32326457] 
[128] 
Zhan, C.; Chen, Y.; Tang, Y.; Wei, G. Green Tea Extracts EGCG and EGC Display Distinct Mechanisms in Disrupting Aβ42 Protofibril. ACS Chem. Neurosci.,  2020, 11(12), 1841-1851.
[http://dx.doi.org/10.1021/acschemneuro.0c00277] [PMID: 32441920] 
[129] 
Xicota, L.; de la Torre, R. (-)-Epigallocatechin-3-gallate and Alzheimer’s disease. In: Genetics, Neurology, Behavior, and Diet in Dementia; Elsevier, 2020; pp. 783-811.
[http://dx.doi.org/10.1016/B978-0-12-815868-5.00050-5] 
[130] 
Mehri, N.; Haddadi, R.; Ganji, M.; Shahidi, S.; Soleimani Asl, S.; Taheri Azandariani, M.; Ranjbar, A. Effects of vitamin D in an animal model of Alzheimer’s disease: behavioral assessment with biochemical investigation of Hippocampus and serum. Metab. Brain Dis.,  2020, 35(2), 263-274.
[http://dx.doi.org/10.1007/s11011-019-00529-7] [PMID: 31853828] 
[131] 
Mastroeni, D.; Grover, A.; Delvaux, E.; Whiteside, C.; Coleman, P.D.; Rogers, J. Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol. Aging,  2010, 31(12), 2025-2037.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.12.005] [PMID: 19117641] 
[132] 
Rahman, M.R.; Islam, T.; Zaman, T.; Shahjaman, M.; Karim, M.R.; Huq, F.; Quinn, J.M.W.; Holsinger, R.M.D.; Gov, E.; Moni, M.A. Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective. Genomics,  2020, 112(2), 1290-1299.
[http://dx.doi.org/10.1016/j.ygeno.2019.07.018] [PMID: 31377428] 
[133] 
Lee, J.; Ryu, H. Epigenetic modification is linked to Alzheimer’s disease: is it a maker or a marker? BMB Rep.,  2010, 43(10), 649-655.
[http://dx.doi.org/10.5483/BMBRep.2010.43.10.649] [PMID: 21034526] 
[134] 
Lord, J.; Cruchaga, C. The epigenetic landscape of Alzheimer’s disease. Nat. Neurosci.,  2014, 17(9), 1138-1140.
[http://dx.doi.org/10.1038/nn.3792] [PMID: 25157507] 
[135] 
Hoeijmakers, L.; Heinen, Y.; van Dam, A-M.; Lucassen, P.J.; Korosi, A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front. Hum. Neurosci.,  2016, 10, 398.
[http://dx.doi.org/10.3389/fnhum.2016.00398] [PMID: 27555812] 
[136] 
Yu, B.; Zhang, K.; Milner, J.J.; Toma, C.; Chen, R.; Scott-Browne, J.P.; Pereira, R.M.; Crotty, S.; Chang, J.T.; Pipkin, M.E.J.N.i.; Wang, W.; Goldrath, A.W. Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation. Nat. Immunol.,  2017, 18(5), 573-582.
[http://dx.doi.org/10.1038/ni.3706] [PMID: 28288100] 
[137] 
Park, J-H.; Choi, Y.; Song, M-J.; Park, K.; Lee, J-J.; Kim, H-P.J.T.J.I. Dynamic long-range chromatin interaction controls expression of IL-21 in CD4+ T cells. J. Immunol.,  2016, 196(10), 4378-4389.
[http://dx.doi.org/10.4049/jimmunol.1500636] [PMID: 27067007] 
[138] 
Pang, K.C.; Dinger, M.E.; Mercer, T.R.; Malquori, L.; Grimmond, S.M.; Chen, W.; Mattick, J.S.J.T.J.I. Genome-wide identification of long noncoding RNAs in CD8+ T cells. J. Immunol.,  2009, 182(12), 7738-7748.
[http://dx.doi.org/10.4049/jimmunol.0900603] [PMID: 19494298] 
[139] 
Carpenter, S.; Aiello, D.; Atianand, M.K.; Ricci, E.P.; Gandhi, P.; Hall, L.L.; Byron, M.; Monks, B.; Henry-Bezy, M.; Lawrence, J.B.; O’Neill, L.A.; Moore, M.J.; Caffrey, D.R.; Fitzgerald, K.A. A long noncoding RNA mediates both activation and repression of immune response genes. Science,  2013, 341(6147), 789-792.
[http://dx.doi.org/10.1126/science.1240925] [PMID: 23907535] 
[140] 
Choi, S-W.; Friso, S. Epigenetics: a new bridge between nutrition and health. Adv. Nutr.,  2010, 1(1), 8-16.
[http://dx.doi.org/10.3945/an.110.1004] [PMID: 22043447] 
[141] 
Malireddy, S.; Kotha, S.R.; Secor, J.D.; Gurney, T.O.; Abbott, J.L.; Maulik, G.; Maddipati, K.R.; Parinandi, N.L.J.A.; Signaling, R. Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease. Antioxid. Redox Signal.,  2012, 17(2), 327-339.
[http://dx.doi.org/10.1089/ars.2012.4600] [PMID: 22404530] 
[142] 
Liu, Z.; Xie, Z.; Jones, W.; Pavlovicz, R.E.; Liu, S.; Yu, J.; Li, P.K.; Lin, J.; Fuchs, J.R.; Marcucci, G.; Li, C.; Chan, K.K. Curcumin is a potent DNA hypomethylation agent. Bioorg. Med. Chem. Lett.,  2009, 19(3), 706-709.
[http://dx.doi.org/10.1016/j.bmcl.2008.12.041] [PMID: 19112019] 
[143] 
Fang, M.Z.; Wang, Y.; Ai, N.; Hou, Z.; Sun, Y.; Lu, H.; Welsh, W.; Yang, C.S. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res.,  2003, 63(22), 7563-7570.
[PMID: 14633667] 
[144] 
Lee, W.J.; Zhu, B.T.J.C. Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis,  2006, 27(2), 269-277.
[http://dx.doi.org/10.1093/carcin/bgi206] [PMID: 16081510] 
[145] 
Majid, S.; Dar, A.A.; Shahryari, V.; Hirata, H.; Ahmad, A.; Saini, S.; Tanaka, Y.; Dahiya, A.V.; Dahiya, R. Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate cancer. Cancer,  2010, 116(1), 66-76.
[PMID: 19885928] 
[146] 
Fang, M.Z.; Chen, D.; Sun, Y.; Jin, Z.; Christman, J.K.; Yang, C.S.J.C.C.R. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin. Cancer Res.,  2005, 11(19 Pt 1), 7033-7041.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-0406] [PMID: 16203797] 
[147] 
Shankar, S.; Kumar, D.; Srivastava, R.K.J.P. Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol. Ther.,  2013, 138(1), 1-17.
[http://dx.doi.org/10.1016/j.pharmthera.2012.11.002] [PMID: 23159372] 
[148] 
Donmez, G.; Wang, D.; Cohen, D.E.; Guarente, L. RETRACTED: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10. Cell,  2010, 142(2), 320-332.
[149] 
Meng, X.; Zhou, J.; Zhao, C-N.; Gan, R-Y.; Li, H-B. Health benefits and molecular mechanisms of resveratrol: A narrative review. Foods,  2020, 9(3), 340.
[http://dx.doi.org/10.3390/foods9030340] [PMID: 32183376] 
[150] 
Ashrafizadeh, M.; Zarrabi, A.; Najafi, M.; Samarghandian, S.; Mohammadinejad, R.; Ahn, K.S. Resveratrol targeting tau proteins, amyloid-beta aggregations, and their adverse effects: An updated review. Phytother. Res.,  2020, 34(11), 2867-2888.
[http://dx.doi.org/10.1002/ptr.6732] [PMID: 32491273] 
[151] 
Braidy, N.; Jugder, B-E.; Poljak, A.; Jayasena, T.; Mansour, H.; Nabavi, S.M.; Sachdev, P.; Grant, R. Resveratrol as a potential therapeutic candidate for the treatment and management of Alzheimer’s disease. Curr. Top. Med. Chem.,  2016, 16(17), 1951-1960.
[http://dx.doi.org/10.2174/1568026616666160204121431] [PMID: 26845555] 
[152] 
Toth, P.; Tarantini, S.; Tucsek, Z.; Ashpole, N.M.; Sosnowska, D.; Gautam, T.; Ballabh, P.; Koller, A.; Sonntag, W.E.; Csiszar, A.; Ungvari, Z. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am. J. Physiol. Heart Circ. Physiol.,  2014, 306(3), H299-H308.
[http://dx.doi.org/10.1152/ajpheart.00744.2013] [PMID: 24322615] 
[153] 
Wiciński, M.; Domanowska, A.; Wódkiewicz, E.; Malinowski, B. Neuroprotective Properties of Resveratrol and Its Derivatives-Influence on Potential Mechanisms Leading to the Development of Alzheimer’s Disease. Int. J. Mol. Sci.,  2020, 21(8), 2749.
[http://dx.doi.org/10.3390/ijms21082749] [PMID: 32326620] 
[154] 
Sousa, J.C.; Santana, A.C.F.; Magalhães, G.J.P. Resveratrol in Alzheimer's disease: a review of pathophysiology and therapeutic potential. Arq. Neuropsiquiatr.,  2020, 78(8), 501-511.
[155] 
Solberg, N.O.; Chamberlin, R.; Vigil, J.R.; Deck, L.M.; Heidrich, J.E.; Brown, D.C.; Brady, C.I.; Vander Jagt, T.A.; Garwood, M.; Bisoffi, M.; Severns, V.; Vander Jagt, D.L.; Sillerud, L.O. Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer’s disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain. J. Alzheimers Dis.,  2014, 40(1), 191-212.
[http://dx.doi.org/10.3233/JAD-131031] [PMID: 24413613] 
[156] 
Zhao, H.F.; Li, N.; Wang, Q.; Cheng, X.J.; Li, X.M.; Liu, T.T. Resveratrol decreases the insoluble Aβ1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience,  2015, 310, 641-649.
[http://dx.doi.org/10.1016/j.neuroscience.2015.10.006] [PMID: 26454022] 
[157] 
Hewlings, S.J.; Kalman, D.S. Curcumin: a review of its’ effects on human health. Foods,  2017, 6(10), 92.
[http://dx.doi.org/10.3390/foods6100092] [PMID: 29065496] 
[158] 
Giacomeli, R.; Izoton, J.C.; Dos Santos, R.B.; Boeira, S.P.; Jesse, C.R.; Haas, S.E. Neuroprotective effects of curcumin lipid-core nanocapsules in a model Alzheimer’s disease induced by β-amyloid 1-42 peptide in aged female mice. Brain Res.,  2019, 1721, 146325.
[http://dx.doi.org/10.1016/j.brainres.2019.146325] [PMID: 31325424] 
[159] 
He, G-L.; Luo, Z.; Yang, J.; Shen, T.T.; Chen, Y.; Yang, X-S. Curcumin ameliorates the reduction effect of PGE2 on fibrillar β-amyloid peptide (1-42)-induced microglial phagocytosis through the inhibition of EP2-PKA signaling in N9 microglial cells. PLoS One,  2016, 11(1), e0147721.
[http://dx.doi.org/10.1371/journal.pone.0147721] [PMID: 26824354] 
[160] 
Xiao, Z.; Zhang, A.; Lin, J.; Zheng, Z.; Shi, X.; Di, W.; Qi, W.; Zhu, Y.; Zhou, G.; Fang, Y. Telomerase: a target for therapeutic effects of curcumin and a curcumin derivative in Aβ1-42 insult in vitro. PLoS One,  2014, 9(7), e101251.
[http://dx.doi.org/10.1371/journal.pone.0101251] [PMID: 24983737] 
[161] 
Ghalebani, L.; Wahlström, A.; Danielsson, J.; Wärmländer, S.K.; Gräslund, A. pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-β peptide. Biochem. Biophys. Res. Commun.,  2012, 421(3), 554-560.
[http://dx.doi.org/10.1016/j.bbrc.2012.04.043] [PMID: 22525674] 
[162] 
Faller, P.; Hureau, C. A bioinorganic view of Alzheimer’s disease: when misplaced metal ions (re)direct the electrons to the wrong target. Chemistry,  2012, 18(50), 15910-15920.
[http://dx.doi.org/10.1002/chem.201202697] [PMID: 23180511] 
[163] 
Lu, W.T.; Sun, S.Q.; Li, Y.; Xu, S.Y.; Gan, S.W.; Xu, J.; Qiu, G.P.; Zhuo, F.; Huang, S.Q.; Jiang, X.L.; Huang, J. Curcumin ameliorates memory deficits by enhancing lactate content and MCT2 expression in APP/PS1 transgenic mouse model of Alzheimer’s disease. Anat. Rec. (Hoboken),  2019, 302(2), 332-338.
[http://dx.doi.org/10.1002/ar.23969] [PMID: 30312017] 
[164] 
Kotani, R.; Urano, Y.; Sugimoto, H.; Noguchi, N. Decrease of amyloid-β levels by curcumin derivative via modulation of amyloid-β protein precursor trafficking. J. Alzheimers Dis.,  2017, 56(2), 529-542.
[http://dx.doi.org/10.3233/JAD-160794] [PMID: 27983550] 
[165] 
Zhang, C.; Browne, A.; Child, D.; Tanzi, R.E. Curcumin decreases amyloid-β peptide levels by attenuating the maturation of amyloid-β precursor protein. J. Biol. Chem.,  2010, 285(37), 28472-28480.
[http://dx.doi.org/10.1074/jbc.M110.133520] [PMID: 20622013] 
[166] 
Solanki, I.; Parihar, P.; Mansuri, M.L.; Parihar, M.S. Flavonoid-based therapies in the early management of neurodegenerative diseases. Adv. Nutr.,  2015, 6(1), 64-72.
[http://dx.doi.org/10.3945/an.114.007500] [PMID: 25593144] 
[167] 
Shi, X.; Zheng, Z.; Li, J.; Xiao, Z.; Qi, W.; Zhang, A.; Wu, Q.; Fang, Y. Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. Neurosci. Lett.,  2015, 594, 105-110.
[http://dx.doi.org/10.1016/j.neulet.2015.03.045] [PMID: 25818332] 
[168] 
Kennaway, D.J. A critical review of melatonin assays: Past and present. J. Pineal Res.,  2019, 67(1), e12572.
[http://dx.doi.org/10.1111/jpi.12572] [PMID: 30919486] 
[169] 
Zhao, D.; Yu, Y.; Shen, Y.; Liu, Q.; Zhao, Z.; Sharma, R.; Reiter, R.J. Melatonin synthesis and function: evolutionary history in animals and plants. Front. Endocrinol. (Lausanne),  2019, 10, 249.
[http://dx.doi.org/10.3389/fendo.2019.00249] [PMID: 31057485] 
[170] 
Mihardja, M.; Roy, J.; Wong, K.Y.; Aquili, L.; Heng, B.C.; Chan, Y.S.; Fung, M.L.; Lim, L.W. Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer’s disease. Ann. N. Y. Acad. Sci.,  2020, 1478(1), 43-62.
[http://dx.doi.org/10.1111/nyas.14436] [PMID: 32700392] 
[171] 
Ali, T.; Kim, M.O. Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus. J. Pineal Res.,  2015, 59(1), 47-59.
[http://dx.doi.org/10.1111/jpi.12238] [PMID: 25858697] 
[172] 
Chinchalongporn, V.; Shukla, M.; Govitrapong, P. Melatonin ameliorates Aβ42 -induced alteration of βAPP-processing secretases via the melatonin receptor through the Pin1/GSK3β/NF-κB pathway in SH-SY5Y cells. J. Pineal Res.,  2018, 64(4), e12470.
[http://dx.doi.org/10.1111/jpi.12470] [PMID: 29352484] 
[173] 
Waly, N.E.; Hallworth, R. Circadian pattern of melatonin MT1 and MT2 receptor localization in the rat suprachiasmatic nucleus. J. Circadian Rhythms,  2015, 13, 1.
[http://dx.doi.org/10.5334/jcr.ab] [PMID: 27103927] 
[174] 
Kong, P-J.; Byun, J-S.; Lim, S-Y.; Lee, J-J.; Hong, S-J.; Kwon, K-J.; Kim, S-S. Melatonin induces Akt phosphorylation through melatonin receptor-and PI3K-dependent pathways in primary astrocytes. Korean J. Physiol. Pharmacol.,  2008, 12(2), 37-41.
[http://dx.doi.org/10.4196/kjpp.2008.12.2.37] [PMID: 20157392] 
[175] 
Shi, J.; Tian, J.; Zhang, X.; Wei, M.; Ni, J.; Li, T.; Zhou, B.; Wu, D.; Wang, P. P1‐407: Influence of gept extract on hippocampal expression of choline acetyltransferase and acetylcholinesterase of APP/PS1 transgenic mice. Alzheimers Dement.,  2014, 10, 462-P463.
[http://dx.doi.org/10.1016/j.jalz.2014.05.650] 
[176] 
Lin, L.; Huang, Q-X.; Yang, S-S.; Chu, J.; Wang, J-Z.; Tian, Q. Melatonin in Alzheimer’s disease. Int. J. Mol. Sci.,  2013, 14(7), 14575-14593.
[http://dx.doi.org/10.3390/ijms140714575] [PMID: 23857055] 
[177] 
Imenshahidi, M.; Hosseinzadeh, H. Berberine and barberry (Berberis vulgaris): A clinical review. Phytother. Res.,  2019, 33(3), 504-523.
[http://dx.doi.org/10.1002/ptr.6252] [PMID: 30637820] 
[178] 
Haghani, M.; Shabani, M.; Tondar, M. The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity. Eur. J. Pharmacol.,  2015, 758, 82-88.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.016] [PMID: 25861937] 
[179] 
Jia, L.; Liu, J.; Song, Z.; Pan, X.; Chen, L.; Cui, X.; Wang, M. Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. J. Pharm. Pharmacol.,  2012, 64(10), 1510-1521.
[http://dx.doi.org/10.1111/j.2042-7158.2012.01529.x] [PMID: 22943182] 
[180] 
Huang, M.; Jiang, X.; Liang, Y.; Liu, Q.; Chen, S.; Guo, Y. Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of β-amyloid in APP/tau/PS1 mouse model of Alzheimer’s disease. Exp. Gerontol.,  2017, 91, 25-33.
[http://dx.doi.org/10.1016/j.exger.2017.02.004] [PMID: 28223223] 
[181] 
de Oliveira, J.S.; Abdalla, F.H.; Dornelles, G.L.; Adefegha, S.A.; Palma, T.V.; Signor, C.; da Silva Bernardi, J.; Baldissarelli, J.; Lenz, L.S.; Magni, L.P.; Rubin, M.A.; Pillat, M.M.; de Andrade, C.M. Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death. Neurotoxicology,  2016, 57, 241-250.
[http://dx.doi.org/10.1016/j.neuro.2016.10.008] [PMID: 27746125] 
[182] 
Magnani, C.; Isaac, V.L.B.; Correa, M.A.; Salgado, H.R.N. Caffeic acid: a review of its potential use in medications and cosmetics. Anal. Methods,  2014, 6(10), 3203-3210.
[http://dx.doi.org/10.1039/C3AY41807C] 
[183] 
Chang, W.; Huang, D.; Lo, Y.M.; Tee, Q.; Kuo, P.; Wu, J.S.; Huang, W.; Shen, S. Protective Effect of Caffeic acid against Alzheimer’s disease pathogenesis via modulating cerebral insulin signaling, β-amyloid accumulation, and synaptic plasticity in hyperinsulinemic rats. J. Agric. Food Chem.,  2019, 67(27), 7684-7693.
[http://dx.doi.org/10.1021/acs.jafc.9b02078] [PMID: 31203623] 
[184] 
Morroni, F.; Sita, G.; Graziosi, A.; Turrini, E.; Fimognari, C.; Tarozzi, A.; Hrelia, P. Neuroprotective effect of caffeic acid phenethyl ester in a mouse model of Alzheimer’s disease involves Nrf2/HO-1 pathway. Aging Dis.,  2018, 9(4), 605-622.
[http://dx.doi.org/10.14336/AD.2017.0903] [PMID: 30090650] 
[185] 
Habtemariam, S. Protective effects of caffeic acid and the Alzheimer’s brain: An update. Mini Rev. Med. Chem.,  2017, 17(8), 667-674.
[http://dx.doi.org/10.2174/1389557516666161130100947] [PMID: 27903226] 
[186] 
Hussain, G.; Huang, J.; Rasul, A.; Anwar, H.; Imran, A.; Maqbool, J.; Razzaq, A.; Aziz, N.; Makhdoom, E.U.H.; Konuk, M.; Sun, T. Putative roles of plant-derived tannins in neurodegenerative and neuropsychiatry disorders: an updated review. Molecules,  2019, 24(12), 2213.
[http://dx.doi.org/10.3390/molecules24122213] [PMID: 31200495] 
[187] 
Chung, K-T.; Wong, T.Y.; Wei, C-I.; Huang, Y-W.; Lin, Y. Tannins and human health: a review. Crit. Rev. Food Sci. Nutr.,  1998, 38(6), 421-464.
[http://dx.doi.org/10.1080/10408699891274273] [PMID: 9759559] 
[188] 
Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer's β-amyloid fibrils in vitro. Biochim. Biophys. Acta,  2004, 1690(3), 193-202.
[189] 
Türkan, F.; Taslimi, P.; Saltan, F.Z. Tannic acid as a natural antioxidant compound: Discovery of a potent metabolic enzyme inhibitor for a new therapeutic approach in diabetes and Alzheimer’s disease. J. Biochem. Mol. Toxicol.,  2019, 33(8), e22340.
[http://dx.doi.org/10.1002/jbt.22340] [PMID: 30974029] 
[190] 
Sylla, T.; Pouységu, L.; Da Costa, G.; Deffieux, D.; Monti, J.P.; Quideau, S. Gallotannins and tannic acid: First chemical syntheses and in vitro inhibitory activity on Alzheimer’s amyloid β-peptide aggregation. Angew. Chem. Int. Ed. Engl.,  2015, 54(28), 8217-8221.
[http://dx.doi.org/10.1002/anie.201411606] [PMID: 26013280] 
[191] 
Garcia-Alloza, M.; Robbins, E.M.; Zhang-Nunes, S.X.; Purcell, S.M.; Betensky, R.A.; Raju, S.; Prada, C.; Greenberg, S.M.; Bacskai, B.J.; Frosch, M.P. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol. Dis.,  2006, 24(3), 516-524.
[http://dx.doi.org/10.1016/j.nbd.2006.08.017] [PMID: 17029828] 
[192] 
Mori, T.; Rezai-Zadeh, K.; Koyama, N.; Arendash, G.W.; Yamaguchi, H.; Kakuda, N.; Horikoshi-Sakuraba, Y.; Tan, J.; Town, T. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J. Biol. Chem.,  2012, 287(9), 6912-6927.
[http://dx.doi.org/10.1074/jbc.M111.294025] [PMID: 22219198] 
[193] 
González-Fuentes, J.; Selva, J.; Moya, C.; Castro-Vázquez, L.; Lozano, M.V.; Marcos, P.; Plaza-Oliver, M.; Rodríguez-Robledo, V.; Santander-Ortega, M.J.; Villaseca-González, N.; Arroyo-Jimenez, M.M. Neuroprotective natural molecules, from food to brain. Front. Neurosci.,  2018, 12, 721.
[http://dx.doi.org/10.3389/fnins.2018.00721] [PMID: 30405328] 
[194] 
Kryscio, R.J.; Abner, E.L.; Caban-Holt, A.; Lovell, M.; Goodman, P.; Darke, A.K.; Yee, M.; Crowley, J.; Schmitt, F.A. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol.,  2017, 74(5), 567-573.
[http://dx.doi.org/10.1001/jamaneurol.2016.5778] [PMID: 28319243] 
[195] 
Lloret, A.; Esteve, D.; Monllor, P.; Cervera-Ferri, A.; Lloret, A. The effectiveness of vitamin E treatment in Alzheimer’s disease. Int. J. Mol. Sci.,  2019, 20(4), 879.
[http://dx.doi.org/10.3390/ijms20040879] [PMID: 30781638] 
[196] 
Boothby, L.A.; Doering, P.L. Vitamin C and vitamin E for Alzheimer’s disease. Ann. Pharmacother.,  2005, 39(12), 2073-2080.
[http://dx.doi.org/10.1345/aph.1E495] [PMID: 16227450] 
[197] 
Heo, J-H.; Hyon-Lee, ; Lee, K.M. The possible role of antioxidant vitamin C in Alzheimer’s disease treatment and prevention. Am. J. Alzheimers Dis. Other Demen.,  2013, 28(2), 120-125.
[http://dx.doi.org/10.1177/1533317512473193] [PMID: 23307795] 
[198] 
Dong, R.; Yang, Q.; Zhang, Y.; Li, J.; Zhang, L.; Zhao, H. Meta- analysis of vitamin C, vitamin E and β-carotene levels in the plasma of Alzheimer’s disease patients. Wei Sheng Yan Jiu,  2018, 47(4), 648-654.
[PMID: 30081996] 
[199] 
Montilla-López, P.; Muñoz-Agueda, M.C.; Feijóo López, M.; Muñoz-Castañeda, J.R.; Bujalance-Arenas, I.; Túnez-Fiñana, I. Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer’s disease induced by okadaic acid in neuroblastoma cells. Eur. J. Pharmacol.,  2002, 451(3), 237-243.
[http://dx.doi.org/10.1016/S0014-2999(02)02151-9] [PMID: 12242084] 
[200] 
Van Dam, F.; Van Gool, W.A. Hyperhomocysteinemia and Alzheimer’s disease: A systematic review. Arch. Gerontol. Geriatr.,  2009, 48(3), 425-430.
[http://dx.doi.org/10.1016/j.archger.2008.03.009] [PMID: 18479766] 
[201] 
de Jager, C.A.; Whitbread, P.; King, E.M.; Martins, C.A.; Smith, A.D.; Jacoby, R.J. P1‐157: TICS‐m and cantab PAL: The ideal telephone screen and memory test for selecting amnestic mild cognitive impairment cases for clinical trials: The oxford project to investigate memory and ageing (optima) vitacog trial experience. Alzheimers Dement.,  2008, 4, T253-T253.
[http://dx.doi.org/10.1016/j.jalz.2008.05.745] 
[202] 
Durga, J.; van Boxtel, M.P.; Schouten, E.G.; Kok, F.J.; Jolles, J.; Katan, M.B.; Verhoef, P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet,  2007, 369(9557), 208-216.
[http://dx.doi.org/10.1016/S0140-6736(07)60109-3] [PMID: 17240287] 
[203] 
Bennett, J.O.; Yu, O.; Heatherly, L.G.; Krishnan, H.B. Accumulation of genistein and daidzein, soybean isoflavones implicated in promoting human health, is significantly elevated by irrigation. J. Agric. Food Chem.,  2004, 52(25), 7574-7579.
[http://dx.doi.org/10.1021/jf049133k] [PMID: 15675806] 
[204] 
Saha, S.; Sadhukhan, P.; Sil, P.C. P., Genistein: a phytoestrogen with multifaceted therapeutic properties. Mini Rev. Med. Chem.,  2014, 14(11), 920-940.
[http://dx.doi.org/10.2174/1389557514666141029233442] [PMID: 25355592] 
[205] 
Uddin, M.S.; Kabir, M.T.; Kabir, T. Emerging signal regulating potential of genistein against Alzheimer’s disease: A promising molecule of interest. Front. Cell Dev. Biol.,  2019, 7, 197.
[http://dx.doi.org/10.3389/fcell.2019.00197] [PMID: 31620438] 
[206] 
Devi, K.P.; Shanmuganathan, B.; Manayi, A.; Nabavi, S.F.; Nabavi, S.M. Molecular and therapeutic targets of genistein in Alzheimer’s disease. Mol. Neurobiol.,  2017, 54(9), 7028-7041.
[http://dx.doi.org/10.1007/s12035-016-0215-6] [PMID: 27796744] 
[207] 
Liao, W.; Jin, G.; Zhao, M.; Yang, H. The effect of genistein on the content and activity of α- and β-secretase and protein kinase C in Aβ-injured hippocampal neurons. Basic Clin. Pharmacol. Toxicol.,  2013, 112(3), 182-185.
[http://dx.doi.org/10.1111/bcpt.12009] [PMID: 22994425] 
[208] 
Xi, Y-D.; Zhang, D-D.; Ding, J.; Yu, H-L.; Yuan, L-H.; Ma, W-W.; Han, J.; Xiao, R. Genistein inhibits Aβ25–35-induced synaptic toxicity and regulates CaMKII/CREB pathway in SH-SY5Y cells. Cell. Mol. Neurobiol.,  2016, 36(7), 1151-1159.
[http://dx.doi.org/10.1007/s10571-015-0311-6] [PMID: 26658733] 
[209] 
Bagheri, M.; Rezakhani, A.; Nyström, S.; Turkina, M.V.; Roghani, M.; Hammarström, P.; Mohseni, S. Amyloid beta(1-40)-induced astrogliosis and the effect of genistein treatment in rat: a three-dimensional confocal morphometric and proteomic study. PLoS One,  2013, 8(10), e76526.
[http://dx.doi.org/10.1371/journal.pone.0076526] [PMID: 24130779] 
[210] 
Fraschini, F.; Demartini, G.; Esposti, D. Pharmacology of silymarin. Clin. Drug Investig.,  2002, 22(1), 51-65.
[http://dx.doi.org/10.2165/00044011-200222010-00007] 
[211] 
Tsai, M-J.; Liao, J-F.; Lin, D-Y.; Huang, M-C.; Liou, D-Y.; Yang, H-C.; Lee, H-J.; Chen, Y-T.; Chi, C-W.; Huang, W-C.; Cheng, H. Silymarin protects spinal cord and cortical cells against oxidative stress and lipopolysaccharide stimulation. Neurochem. Int.,  2010, 57(8), 867-875.
[http://dx.doi.org/10.1016/j.neuint.2010.09.005] [PMID: 20868716] 
[212] 
Yaghmaei, P.; Azarfar, K.; Dezfulian, M.; Ebrahim-Habibi, A. Silymarin effect on amyloid-β plaque accumulation and gene expression of APP in an Alzheimer’s disease rat model. Daru,  2014, 22(1), 24.
[http://dx.doi.org/10.1186/2008-2231-22-24] [PMID: 24460990] 
[213] 
Kumar, J.; Park, K.-C.; Awasthi, A.; Prasad, B. Silymarin extends lifespan and reduces proteotoxicity in C. elegans Alzheimer’s model. CNS Neurol. Disord. Drug Targets,  2015, 14(2), 295-302.
[214] 
Duan, S.; Guan, X.; Lin, R.; Liu, X.; Yan, Y.; Lin, R.; Zhang, T.; Chen, X.; Huang, J.; Sun, X.; Li, Q.; Fang, S.; Xu, J.; Yao, Z.; Gu, H. Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: a dual-target drug for the treatment of Alzheimer’s disease. Neurobiol. Aging,  2015, 36(5), 1792-1807.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.02.002] [PMID: 25771396] 
[215] 
Li, C.; Li, Q.; Mei, Q.; Lu, T. Pharmacological effects and pharmacokinetic properties of icariin, the major bioactive component in Herba Epimedii. Life Sci.,  2015, 126, 57-68.
[http://dx.doi.org/10.1016/j.lfs.2015.01.006] [PMID: 25634110] 
[216] 
Wu, J.; Qu, J-Q.; Zhou, Y-J.; Zhou, Y-J.; Li, Y-Y.; Huang, N-Q.; Deng, C-M.; Luo, Y. Icariin improves cognitive deficits by reducing the deposition of β-amyloid peptide and inhibition of neurons apoptosis in SAMP8 mice. Neuroreport,  2020, 31(9), 663-671.
[http://dx.doi.org/10.1097/WNR.0000000000001466] [PMID: 32427716] 
[217] 
Sharma, S.; Khan, V.; Najmi, A.K.; Alam, O.; Haque, S.E. Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear Factor-Like 2 activation. Pharmacogn. Mag.,  2018, 14(55), 227.
[http://dx.doi.org/10.4103/pm.pm_469_17] 
[218] 
Zhang, B.; Wang, G.; He, J.; Yang, Q.; Li, D.; Li, J.; Zhang, F. Icariin attenuates neuroinflammation and exerts dopamine neuroprotection via an Nrf2-dependent manner. J. Neuroinflammation,  2019, 16(1), 92.
[http://dx.doi.org/10.1186/s12974-019-1472-x] [PMID: 31010422] 
[219] 
Sheng, C.; Xu, P.; Zhou, K.; Deng, D.; Zhang, C.; Wang, Z. Icariin attenuates synaptic and cognitive deficits in an Aβ1–42-induced rat model of Alzheimer’s disease. BioMed research international,  2017, 2017, 7464872.
[http://dx.doi.org/10.1155/2017/7464872] 
[220] 
Chen, Y.; Han, S.; Huang, X.; Ni, J.; He, X. The protective effect of icariin on mitochondrial transport and distribution in primary hippocampal neurons from 3× Tg-AD mice. Int. J. Mol. Sci.,  2016, 17(2), 163.
[http://dx.doi.org/10.3390/ijms17020163] [PMID: 26828481] 
[221] 
Zhang, L.; Shen, C.; Chu, J.; Zhang, R.; Li, Y.; Li, L. Icariin decreases the expression of APP and BACE-1 and reduces the β-amyloid burden in an APP transgenic mouse model of Alzheimer’s disease. Int. J. Biol. Sci.,  2014, 10(2), 181-191.
[http://dx.doi.org/10.7150/ijbs.6232] [PMID: 24550686] 
[222] 
Li, X-A.; Ho, Y-S.; Chen, L.; Hsiao, W.L. The protective effects of icariin against the homocysteine-induced neurotoxicity in the primary embryonic cultures of rat cortical neurons. Molecules,  2016, 21(11), 1557.
[http://dx.doi.org/10.3390/molecules21111557] [PMID: 27879670] 
[223] 
Singh, J.C.H.; Kakalij, R.M.; Kshirsagar, R.P.; Kumar, B.H.; Komakula, S.S.B.; Diwan, P.V. Cognitive effects of vanillic acid against streptozotocin-induced neurodegeneration in mice. Pharm. Biol.,  2015, 53(5), 630-636.
[http://dx.doi.org/10.3109/13880209.2014.935866] [PMID: 25472801] 
[224] 
Huang, X.; Xi, Y.; Mao, Z.; Chu, X.; Zhang, R.; Ma, X.; Ni, B.; Cheng, H.; You, H. Vanillic acid attenuates cartilage degeneration by regulating the MAPK and PI3K/AKT/NF-κB pathways. Eur. J. Pharmacol.,  2019, 859, 172481.
[http://dx.doi.org/10.1016/j.ejphar.2019.172481] [PMID: 31228458] 
[225] 
Amin, F.U.; Shah, S.A.; Kim, M.O. Vanillic acid attenuates Aβ1-42-induced oxidative stress and cognitive impairment in mice. Sci. Rep.,  2017, 7, 40753.
[http://dx.doi.org/10.1038/srep40753] [PMID: 28098243] 
[226] 
Villareal, M.O.; Sasaki, K.; Margout, D.; Savry, C.; Almaksour, Z.; Larroque, M.; Isoda, H. Neuroprotective effect of Picholine virgin olive oil and its hydroxycinnamic acids component against β-amyloid-induced toxicity in SH-SY5Y neurotypic cells. Cytotechnology,  2016, 68(6), 2567-2578.
[http://dx.doi.org/10.1007/s10616-016-9980-3] [PMID: 27155966] 
[227] 
Cox, K.H.; Pipingas, A.; Scholey, A.B. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J. Psychopharmacol.,  2015, 29(5), 642-651.
[http://dx.doi.org/10.1177/0269881114552744] [PMID: 25277322] 
[228] 
Small, G.W.; Siddarth, P.; Li, Z.; Miller, K.J.; Ercoli, L.; Emerson, N.D.; Martinez, J.; Wong, K-P.; Liu, J.; Merrill, D.A.; Chen, S.T.; Henning, S.M.; Satyamurthy, N.; Huang, S.C.; Heber, D.; Barrio, J.R. Memory and brain amyloid and tau effects of a bioavailable form of curcumin in non-demented adults: a double-blind, placebo-controlled 18-month trial. Am. J. Geriatr. Psychiatry,  2018, 26(3), 266-277.
[http://dx.doi.org/10.1016/j.jagp.2017.10.010] [PMID: 29246725] 
[229] 
Krikorian, R.; Shidler, M.D.; Nash, T.A.; Kalt, W.; Vinqvist- Tymchuk, M.R.; Shukitt-Hale, B.; Joseph, J.A. Blueberry supplementation improves memory in older adults. J. Agric. Food Chem.,  2010, 58(7), 3996-4000.
[http://dx.doi.org/10.1021/jf9029332] [PMID: 20047325] 
[230] 
Moussa, C.; Hebron, M.; Huang, X.; Ahn, J.; Rissman, R.A.; Aisen, P.S.; Turner, R.S. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflammation,  2017, 14(1), 1.
[http://dx.doi.org/10.1186/s12974-016-0779-0] [PMID: 28086917] 
[231] 
Zhu, C.W.; Grossman, H.; Neugroschl, J.; Parker, S.; Burden, A.; Luo, X.; Sano, M. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: A pilot study. Alzheimers Dement. (N. Y.),  2018, 4, 609-616.
[http://dx.doi.org/10.1016/j.trci.2018.09.009] [PMID: 30480082] 
[232] 
Ihl, R.; Tribanek, M.; Bachinskaya, N.; Group, G.S. GOTADAY Study Group. Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer’s disease and vascular dementia: results from a randomised controlled trial. Pharmacopsychiatry,  2012, 45(2), 41-46.
[http://dx.doi.org/10.1055/s-0031-1291217] [PMID: 22086747] 
[233] 
Rapp, M.; Burkart, M.; Kohlmann, T.; Bohlken, J. Similar treatment outcomes with Ginkgo biloba extract EGb 761 and donepezil in Alzheimer’s dementia in very old age: A retrospective observational study. Int. J. Clin. Pharmacol. Ther.,  2018, 56(3), 130-133.
[http://dx.doi.org/10.5414/CP203103] [PMID: 29319499] 
[234] 
Oken, B.S.; Storzbach, D.M.; Kaye, J.A. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch. Neurol.,  1998, 55(11), 1409-1415.
[http://dx.doi.org/10.1001/archneur.55.11.1409] [PMID: 9823823] 
[235] 
DeKosky, S.T.; Williamson, J.D.; Fitzpatrick, A.L.; Kronmal, R.A.; Ives, D.G.; Saxton, J.A.; Lopez, O.L.; Burke, G.; Carlson, M.C.; Fried, L.P.; Kuller, L.H.; Robbins, J.A.; Tracy, R.P.; Woolard, N.F.; Dunn, L.; Snitz, B.E.; Nahin, R.L.; Furberg, C.D. Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA,  2008, 300(19), 2253-2262.
[http://dx.doi.org/10.1001/jama.2008.683] [PMID: 19017911] 
[236] 
Snitz, B.E.; O’Meara, E.S.; Carlson, M.C.; Arnold, A.M.; Ives, D.G.; Rapp, S.R.; Saxton, J.; Lopez, O.L.; Dunn, L.O.; Sink, K.M.; DeKosky, S.T. Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA,  2009, 302(24), 2663-2670.
[http://dx.doi.org/10.1001/jama.2009.1913] [PMID: 20040554] 
[237] 
Feng, L.; Li, J.; Ng, T-P.; Lee, T-S.; Kua, E-H.; Zeng, Y. Tea drinking and cognitive function in oldest-old Chinese. J. Nutr. Health Aging,  2012, 16(9), 754-758.
[http://dx.doi.org/10.1007/s12603-012-0077-1] [PMID: 23131816] 
[238] 
Ng, T-P.; Feng, L.; Niti, M.; Kua, E-H.; Yap, K-B. Tea consumption and cognitive impairment and decline in older Chinese adults. Am. J. Clin. Nutr.,  2008, 88(1), 224-231.
[http://dx.doi.org/10.1093/ajcn/88.1.224] [PMID: 18614745] 
[239] 
Gu, Y-J.; He, C-H.; Li, S.; Zhang, S-Y.; Duan, S-Y.; Sun, H-P.; Shen, Y-P.; Xu, Y.; Yin, J-Y.; Pan, C-W. Tea consumption is associated with cognitive impairment in older Chinese adults. Aging Ment. Health,  2018, 22(9), 1232-1238.
[http://dx.doi.org/10.1080/13607863.2017.1339779] [PMID: 28636413] 
[240] 
Miller, M.G.; Hamilton, D.A.; Joseph, J.A.; Shukitt-Hale, B. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. Eur. J. Nutr.,  2018, 57(3), 1169-1180.
[http://dx.doi.org/10.1007/s00394-017-1400-8] [PMID: 28283823] 
[241] 
Turner, R.S.; Thomas, R.G.; Craft, S.; van Dyck, C.H.; Mintzer, J.; Reynolds, B.A.; Brewer, J.B.; Rissman, R.A.; Raman, R.; Aisen, P.S. Alzheimer’s Disease Cooperative Study. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology,  2015, 85(16), 1383-1391.
[http://dx.doi.org/10.1212/WNL.0000000000002035] [PMID: 26362286] 
[242] 
Voulgaropoulou, S.D.; van Amelsvoort, T.A.M.J.; Prickaerts, J.; Vingerhoets, C. The effect of curcumin on cognition in Alzheimer’s disease and healthy aging: A systematic review of pre-clinical and clinical studies. Brain Res.,  2019, 1725, 146476.
[http://dx.doi.org/10.1016/j.brainres.2019.146476] [PMID: 31560864] 
[243] 
Asayama, K.; Yamadera, H.; Ito, T.; Suzuki, H.; Kudo, Y.; Endo, S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J. Nippon Med. Sch.,  2003, 70(4), 334-341.
[http://dx.doi.org/10.1272/jnms.70.334] [PMID: 12928714] 
[244] 
Riemersma-van der Lek, R.F.; Swaab, D.F.; Twisk, J.; Hol, E.M.; Hoogendijk, W.J.; Van Someren, E.J. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA,  2008, 299(22), 2642-2655.
[http://dx.doi.org/10.1001/jama.299.22.2642] [PMID: 18544724] 
[245] 
Brusco, L.I.; Márquez, M.; Cardinali, D.P. Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuroendocrinol. Lett.,  2000, 21(1), 39-42.
[PMID: 11455329] 
[246] 
Brusco, L.I.; Márquez, M.; Cardinali, D.P. Monozygotic twins with Alzheimer’s disease treated with melatonin: Case report. J. Pineal Res.,  1998, 25(4), 260-263.
[http://dx.doi.org/10.1111/j.1600-079X.1998.tb00396.x] [PMID: 9885996] 
[247] 
Gleason, C.E.; Fischer, B.L.; Dowling, N.M.; Setchell, K.D.; Atwood, C.S.; Carlsson, C.M.; Asthana, S. Cognitive effects of soy isoflavones in patients with Alzheimer’s disease. J. Alzheimers Dis.,  2015, 47(4), 1009-1019.
[http://dx.doi.org/10.3233/JAD-142958] [PMID: 26401779] 
[248] 
Bachinskaya, N.; Hoerr, R.; Ihl, R. Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb 761. Findings from a randomized controlled trial. Neuropsychiatr. Dis. Treat.,  2011, 7, 209-215.
[PMID: 21573082] 
[249] 
Gavrilova, S.I.; Preuss, U.W.; Wong, J.W.; Hoerr, R.; Kaschel, R.; Bachinskaya, N.; Group, G.S. GIMCIPlus Study Group. Efficacy and safety of Ginkgo biloba extract EGb 761 in mild cognitive impairment with neuropsychiatric symptoms: a randomized, placebo-controlled, double-blind, multi-center trial. Int. J. Geriatr. Psychiatry,  2014, 29(10), 1087-1095.
[http://dx.doi.org/10.1002/gps.4103] [PMID: 24633934] 
[250] 
Xu, S-S.; Gao, Z-X.; Weng, Z.; Du, Z-M.; Xu, W-A.; Yang, J-S.; Zhang, M-L.; Tong, Z-H.; Fang, Y-S.; Chai, X-S. Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease. Zhongguo Yao Li Xue Bao,  1995, 16(5), 391-395.
[PMID: 8701750] 
[251] 
Xu, S-S.; Cai, Z-Y.; Qu, Z-W.; Yang, R-M.; Cai, Y-L.; Wang, G-Q.; Su, X-Q.; Zhong, X-S.; Cheng, R-Y.; Xu, W-A.; Li, J.X.; Feng, B. Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Zhongguo Yao Li Xue Bao,  1999, 20(6), 486-490.
[PMID: 10678137] 
[252] 
Rafii, M.S.; Walsh, S.; Little, J.T.; Behan, K.; Reynolds, B.; Ward, C.; Jin, S.; Thomas, R.; Aisen, P.S. Alzheimer’s Disease Cooperative Study. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology,  2011, 76(16), 1389-1394.
[http://dx.doi.org/10.1212/WNL.0b013e318216eb7b] [PMID: 21502597] 
[253] 
Del Prado-Audelo, M.L.; Caballero-Florán, I.H.; Meza-Toledo, J.A.; Mendoza-Muñoz, N.; González-Torres, M.; Florán, B.; Cortés, H.; Leyva-Gómez, G.; Leyva-Gómez, G. Formulations of curcumin nanoparticles for brain diseases. Biomolecules,  2019, 9(2), 56.
[http://dx.doi.org/10.3390/biom9020056] [PMID: 30743984] 
[254] 
Jones, D.; Caballero, S.; Davidov-Pardo, G. Bioavailability of nanotechnology-based bioactives and nutraceuticals.Advances in food and nutrition research; Elsevier, 2019, Vol. 88, pp. 235-273.
[255] 
Fonseca-Santos, B.; Gremião, M.P.D.; Chorilli, M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease. Int. J. Nanomedicine,  2015, 10, 4981-5003.
[http://dx.doi.org/10.2147/IJN.S87148] [PMID: 26345528] 
[256] 
Khan, S.A.; Rehman, S.; Nabi, B.; Iqubal, A.; Nehal, N.; Fahmy, U.A.; Kotta, S.; Baboota, S.; Md, S.; Ali, J. Boosting the Brain Delivery of Atazanavir through Nanostructured Lipid Carrier-Based Approach for Mitigating NeuroAIDS. Pharmaceutics,  2020, 12(11), 1059.
[http://dx.doi.org/10.3390/pharmaceutics12111059] [PMID: 33172119] 
[257] 
Harilal, S.; Jose, J.; Parambi, D.G.T.; Kumar, R.; Mathew, G.E.; Uddin, M.S.; Kim, H.; Mathew, B. Advancements in nanotherapeutics for Alzheimer’s disease: current perspectives. J. Pharm. Pharmacol.,  2019, 71(9), 1370-1383.
[http://dx.doi.org/10.1111/jphp.13132] [PMID: 31304982] 
[258] 
Mourtas, S.; Lazar, A.N.; Markoutsa, E.; Duyckaerts, C.; Antimisiaris, S.G. Multifunctional nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. Eur. J. Med. Chem.,  2014, 80, 175-183.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.050] [PMID: 24780594] 
[259] 
Hadavi, D.; Poot, A.A. Biomaterials for the Treatment of Alzheimer’s Disease. Front. Bioeng. Biotechnol.,  2016, 4, 49.
[http://dx.doi.org/10.3389/fbioe.2016.00049] [PMID: 27379232] 
[260] 
Doggui, S.; Dao, L.; Ramassamy, C. Potential of drug-loaded nanoparticles for Alzheimer’s disease: diagnosis, prevention and treatment. Ther. Deliv.,  2012, 3(9), 1025-1027.
[http://dx.doi.org/10.4155/tde.12.84] [PMID: 23035588] 
[261] 
Cheng, K.K.; Yeung, C.F.; Ho, S.W.; Chow, S.F.; Chow, A.H.; Baum, L. Highly stabilized curcumin nanoparticles tested in an in vitro blood-brain barrier model and in Alzheimer’s disease Tg2576 mice. AAPS J.,  2013, 15(2), 324-336.
[http://dx.doi.org/10.1208/s12248-012-9444-4] [PMID: 23229335] 
[262] 
Fan, S.; Zheng, Y.; Liu, X.; Fang, W.; Chen, X.; Liao, W.; Jing, X.; Lei, M.; Tao, E.; Ma, Q.; Zhang, X.; Guo, R.; Liu, J. Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer’s disease. Drug Deliv.,  2018, 25(1), 1091-1102.
[http://dx.doi.org/10.1080/10717544.2018.1461955] [PMID: 30107760] 
[263] 
Sun, D.; Li, N.; Zhang, W.; Zhao, Z.; Mou, Z.; Huang, D.; Liu, J.; Wang, W. Design of PLGA-functionalized quercetin nanoparticles for potential use in Alzheimer’s disease. Colloids Surf. B Biointerfaces,  2016, 148, 116-129.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.052] [PMID: 27591943] 
[264] 
Nirale, P.; Paul, A.; Yadav, K.S. Nanoemulsions for targeting the neurodegenerative diseases: Alzheimer’s, Parkinson’s and Prion’s. Life Sci.,  2020, 245, 117394.
[http://dx.doi.org/10.1016/j.lfs.2020.117394] [PMID: 32017870] 
[265] 
Sood, S.; Jain, K.; Gowthamarajan, K. Intranasal delivery of curcumin–/INS; donepezil nanoemulsion for brain targeting in Alzheimer’s disease. J. Neurol. Sci.,  2013, 333, e316-e317.
[http://dx.doi.org/10.1016/j.jns.2013.07.1182] 
[266] 
Md, S.; Gan, S.Y.; Haw, Y.H.; Ho, C.L.; Wong, S.; Choudhury, H. In vitro neuroprotective effects of naringenin nanoemulsion against β-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. Int. J. Biol. Macromol.,  2018, 118(Pt A), 1211-1219.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.06.190] [PMID: 30001606] 
[267] 
Yusuf, M.; Khan, M.; Khan, R.A.; Ahmed, B. Preparation, characterization, in vivo and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer’s disease model. J. Drug Target.,  2013, 21(3), 300-311.
[http://dx.doi.org/10.3109/1061186X.2012.747529] [PMID: 23231324] 
[268] 
Loureiro, J.A.; Andrade, S.; Duarte, A.; Neves, A.R.; Queiroz, J.F.; Nunes, C.; Sevin, E.; Fenart, L.; Gosselet, F.; Coelho, M.A.; Pereira, M.C. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules,  2017, 22(2), 277.
[http://dx.doi.org/10.3390/molecules22020277] [PMID: 28208831] 
[269] 
Alexander, H. R.; Syed Alwi, S. S.; Yazan, L. S.; Zakarial Ansar, F. H.; Ong, Y. S. Migration and proliferation effects of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) and thymoquinone (TQ) on in vitro wound healing models. Evidence-Based Complementary and Alternative Medicine, 2019.
[270] 
Sadegh Malvajerd, S.; Izadi, Z.; Azadi, A.; Kurd, M.; Derakhshankhah, H.; Sharifzadeh, M.; Akbari Javar, H.; Hamidi, M. Neuroprotective potential of curcumin-loaded nanostructured lipid carrier in an animal model of Alzheimer’s disease: behavioral and biochemical evidence. J. Alzheimers Dis.,  2019, 69(3), 671-686.
[http://dx.doi.org/10.3233/JAD-190083] [PMID: 31156160] 
[271] 
Cano, A.; Ettcheto, M.; Chang, J-H.; Barroso, E.; Espina, M.; Kühne, B.A.; Barenys, M.; Auladell, C.; Folch, J.; Souto, E.B.; Camins, A.; Turowski, P.; García, M.L. Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer’s disease mice model. J. Control. Release,  2019, 301, 62-75.
[http://dx.doi.org/10.1016/j.jconrel.2019.03.010] [PMID: 30876953] 
[272] 
Huo, X.; Zhang, Y.; Jin, X.; Li, Y.; Zhang, L. A novel synthesis of selenium nanoparticles encapsulated PLGA nanospheres with curcumin molecules for the inhibition of amyloid β aggregation in Alzheimer’s disease. J. Photochem. Photobiol. B,  2019, 190, 98-102.
[http://dx.doi.org/10.1016/j.jphotobiol.2018.11.008] [PMID: 30504054] 
[273] 
Cheng, K.K.; Chan, P.S.; Fan, S.; Kwan, S.M.; Yeung, K.L.; Wáng, Y-X.J.; Chow, A.H.L.; Wu, E.X.; Baum, L. Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer’s disease mice using magnetic resonance imaging (MRI). Biomaterials,  2015, 44, 155-172.
[http://dx.doi.org/10.1016/j.biomaterials.2014.12.005] [PMID: 25617135] 
[274] 
Lazar, A.N.; Mourtas, S.; Youssef, I.; Parizot, C.; Dauphin, A.; Delatour, B.; Antimisiaris, S.G.; Duyckaerts, C. Curcumin-conjugated nanoliposomes with high affinity for Aβ deposits: possible applications to Alzheimer disease. Nanomedicine (Lond.),  2013, 9(5), 712-721.
[http://dx.doi.org/10.1016/j.nano.2012.11.004] [PMID: 23220328] 
[275] 
Bondi, M.; Montana, G.; Craparo, E.; Picone, P.; Capuano, G.; Carlo, M.; Giammona, G. Ferulic acid-loaded lipid nanostructures as drug delivery systems for Alzheimer’s disease: preparation, characterization and cytotoxicity studies. Curr. Nanosci.,  2009, 5(1), 26-32.
[http://dx.doi.org/10.2174/157341309787314656] 
[276] 
Yang, C-R.; Zhao, X-L.; Hu, H-Y.; Li, K-X.; Sun, X.; Li, L.; Chen, D-W. Preparation, optimization and characteristic of huperzine a loaded nanostructured lipid carriers. Chem. Pharm. Bull. (Tokyo),  2010, 58(5), 656-661.
[http://dx.doi.org/10.1248/cpb.58.656] [PMID: 20460792] 
[277] 
Frozza, R.L.; Salbego, C.; Bernardi, A.; Hoppe, J.B.; Meneghetti, A.; Battastini, A.M.; Guterres, S.; Pohlmann, A. P1‐006: Incorporation of resveratrol into lipid‐core nanocapsules improves its cerebral bioavailability and reduces the Aβ‐induced toxicity. Alzheimers Dement.,  2011, 7, S114-S114.
[http://dx.doi.org/10.1016/j.jalz.2011.05.286] 
[278] 
Meng, F.; Asghar, S.; Gao, S.; Su, Z.; Song, J.; Huo, M.; Meng, W.; Ping, Q.; Xiao, Y. A novel LDL-mimic nanocarrier for the targeted delivery of curcumin into the brain to treat Alzheimer’s disease. Colloids Surf. B Biointerfaces,  2015, 134, 88-97.
[http://dx.doi.org/10.1016/j.colsurfb.2015.06.025] [PMID: 26162977] 
[279] 
Sood, S.; Jain, K.; Gowthamarajan, K. Curcumin-donepezil–loaded nanostructured lipid carriers for intranasal delivery in an Alzheimer’s disease model. Alzheimers Dement.,  2013, 4(9), 299.
[http://dx.doi.org/10.1016/j.jalz.2013.05.609] 
[280] 
Gupta, R.C. Nutraceuticals: efficacy, safety and toxicity.Academic Press, 2016. 
[281] 
Da Costa, J.P. A current look at nutraceuticals–key concepts and future prospects. Trends Food Sci. Technol.,  2017, 62, 68-78.
[http://dx.doi.org/10.1016/j.tifs.2017.02.010] 
[282] 
Filipiak-Szok, A.; Kurzawa, M.; Szłyk, E. Determination of toxic metals by ICP-MS in Asiatic and European medicinal plants and dietary supplements. J. Trace Elem. Med. Biol.,  2015, 30, 54-58.
[http://dx.doi.org/10.1016/j.jtemb.2014.10.008] [PMID: 25467854] 
Rights & Permissions Print Cite
Article Metrics
44
5
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
For Visitors
DOI https://dx.doi.org/10.2174/1874467214666210309115605	Print ISSN 1874-4672
Publisher Name Bentham Science Publisher	Online ISSN 1874-4702
Current Molecular Pharmacology

Nutraceuticals and their Derived Nano-Formulations for the Prevention and Treatment of Alzheimer's Disease

Abstract

Graphical Abstract

Advances in the Diagnosis and Treatment of Head and Neck Disease

New Cell Death Regulation Drugs for Cardiovascular Diseases

Current Molecular Pharmacology

Nutraceuticals and their Derived Nano-Formulations for the Prevention and Treatment of Alzheimer's Disease

Abstract

Graphical Abstract

Call for Papers in Thematic Issues

Advances in the Diagnosis and Treatment of Head and Neck Disease

New Cell Death Regulation Drugs for Cardiovascular Diseases

Related Journals

Related Books

Related Articles
