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Exploring the Neuroprotective Potential of 5-Azacytidine on the Streptozotocin-Induced Rat Model of Alzheimer’s Disease
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DOI：10.1021/acschemneuro.6c00234.png)
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Abstract
En 中文
Alzheimer’s disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1–42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.
Keywords:
Cell signaling
Genetics
Inhibition
Nervous system diseases
Peptides and proteins
Alzheimer’s disease
DNMT1-mediated hypermethylation
5-azacytidine
Wnt/β-catenin signaling pathway
neuroprotective effect
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