Title:Toll-Like Receptors in Alzheimer's Disease: A Therapeutic Perspective
Volume: 13
Issue: 9
Author(s): Maria E. Gambuzza, Vincenza Sofo, Francesca M. Salmeri, Luca Soraci, Silvia Marino and Placido Bramanti
Affiliation:
Keywords:
Alzheimer’s disease, amyloid-beta, autophagy, inflammation, phagocytosis, Toll-like receptors, Toll-like receptortargeted
therapeutics.
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder mainly characterized by amyloid-β (Aβ) plaques,
neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. Emerging data highlight the
involvement of innate immunity, that has been shown to play opposing roles during the AD progression. Activated
microglia and reactive astrocytes exert neuroprotection mediated through Aβphagocytosis in the early stage, whereas, as
the disease progresses, they fail in Aβclearance and exert detrimental effects, including neuroinflammation and
neurodegeneration. Specific toll-like receptors (TLRs) and coreceptors can directly or indirectly be activated to induce Aβ
uptake or inflammatory responses, depending on the disease stage. Fibrillar Aβcan directly interact with TLR2, TLR4,
and CD14 to induce microglial Aβphagocytosis in the beginning stages, and neuroinflammatory responses in the late
stages. Early TLR3-mediated signal enhances neuronal Aβautophagy, although it increases neuronal apoptosis in the late
AD stage. Similarly, TLR7, TLR8 and TLR9 can enhance microglial Aβuptake in the early stage, but over time they
contribute to neuroinflammation. Therefore, TLRs, and in particular TLR2 and TLR4, represent a suitable target for
therapeutic intervention within the disease progression and targeting them carefully could increase Aβ autophagy and
phagocytosis or reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity
have been developed, and many of them could have a therapeutic benefit in AD patients. This paper outlines the role of
specific TLRs in AD, also focusing on TLR-targeted compounds yet indicated for the treatment of other inflammatory
diseases, that could be used to treat the different stages of the disease.
