Bathla Shveta, Datta Dibyadeep, Bolat Dinara, Woo Elizabeth, Duque Alvaro, Arellano Jon I, Arnsten Amy F T, Nairn Angus C
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States.
Front Aging Neurosci. 2025 Apr 29;17:1549770. doi: 10.3389/fnagi.2025.1549770. eCollection 2025.
Tau pathology in sporadic Alzheimer's disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation.
Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways using biochemical and immunohistochemistry.
Our findings reveal an age-related decrease in PDE4 phosphodiesterase that hydrolyzes cAMP and increases in calpain-2 and glutamate carboxypeptidase II that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau).
These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, may prime tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.
散发性阿尔茨海默病（AD）中的tau病理遵循一种独特模式，始于内嗅皮质（ERC）并扩散至相互连接的脑区。以可溶性磷酸化tau为特征的早期tau病理，由于死后大脑中磷酸化迅速消失，在人体尸检研究中很难进行。
恒河猴自然会出现与年龄相关的类似人类AD的tau病理，为研究早期tau病因提供了理想模型。本研究考察了猕猴ERC中tau病理的分子过程，利用生化和免疫组织化学方法重点研究钙信号通路和炎症信号通路。
我们的研究结果显示，随着多个表位（pS214 - tau、pT181 - tau、pT217 - tau）早期tau过度磷酸化的同时，水解cAMP的磷酸二酯酶4（PDE4）出现与年龄相关的减少，而钙蛋白酶2和谷氨酸羧肽酶II则增加。
这些结果表明，从中年开始，ERC中钙信号失调可能引发tau过度磷酸化，这可能推动AD的早期阶段，增进了我们对ERC易损性如何导致AD神经退行性变的理解。
