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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer’s Disease: An Experimental and Bioinformatics Study

Author(s): Wei Ma, Kui Lu, Hua-Min Liang and Jin-Yuan Zhang*

Volume 20, Issue 9, 2023

Published on: 11 January, 2024

Page: [648 - 659] Pages: 12

DOI: 10.2174/0115672050276594231229050906

Price: $65

Abstract

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.

Keywords: Alzheimer’s disease (AD), synapsin 1 (SYN1), GEO database, oxidative stress, inflammatory response, cAMP signaling pathway.

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