Title:Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in
Rats with Alzheimer’s Disease: An Experimental and Bioinformatics
Study
Volume: 20
Issue: 9
关键词:
阿尔茨海默病(AD)，突触素1 (SYN1)， GEO数据库，氧化应激，炎症反应，cAMP信号通路。
摘要:
Background:: Alzheimer’s disease (AD) is a persistent neuropathological injury that
manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation,
and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible
for the pathology of AD.
Objective: This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential
regulatory mechanisms.
Methods: The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused
on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of
Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were
treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated
behavior was validated using multiple experiments (water maze test and object recognition
test). SYN1’s repairing effect on the important factors in AD was confirmed by detecting the
concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α),
neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and
markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species
(ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine
AD-related signaling pathways after SYN1 overexpression.
Results: Differential expression analysis yielded a total of 545 differentially expressed genes, of
which four were upregulated and 541 were downregulated. The enriched pathways were basically
focused on synaptic functions, and the analysis of the protein– protein interaction network focused
on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities
of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water
maze, the significantly extended dwell time in the third quadrant, and the increased number of
crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to
explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was
activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion
of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative
stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory
factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1
overexpression.
Conclusion: SYN1 overexpression improves cognitive function and promotes the release of various
neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses
through cAMP signaling pathway activation. These findings may provide a theoretical basis for
the targeted diagnosis and treatment of AD.
