High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer's Disease Via a Specific Tau Phosphorylation Pattern.
Y Ito, S Takeda, T Nakajima, A Oyama, H Takeshita, K Miki, Y Takami, Y Takeya, M Shimamura, H Rakugi, R Morishita
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引用次数: 0
Abstract
Background: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer's disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.
Objective: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.
Design: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.
Results: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.
Conclusion: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.
背景:流行病学证据表明,糖尿病与阿尔茨海默病(AD)风险增加之间存在明显的关联。磷酸化 tau 聚合体在大脑中的积累是阿尔茨海默病的主要神经病理学特征,与神经变性和认知能力下降有关。临床和实验研究表明,糖尿病会影响 tau 病理学的发展;然而,其潜在的分子机制仍然未知:在本研究中,我们使用一种独特的糖尿病 AD 小鼠模型来研究糖尿病脑中发生的 tau 磷酸化模式的变化:Tau转基因小鼠(n = 24)被喂食高脂肪饮食以模拟糖尿病。这些小鼠出现了明显的肥胖、严重的胰岛素抵抗和轻度高血糖,从而导致了与高磷酸化 tau 聚集体积累相关的早发性神经退行性变和行为障碍:结果:全面的磷酸化蛋白质组分析发现,糖尿病性AD小鼠大脑中存在独特的tau磷酸化特征。对磷酸蛋白组学数据进行的生物信息学分析揭示了参与糖尿病与AD相互作用的tau相关激酶和细胞信号通路:这些发现提供了潜在的新靶点,可用于开发基于tau的疗法和用于AD的生物标记物。
期刊介绍:
The JPAD « Journal of Prevention of Alzheimer’Disease » will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including : neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.
JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.