Bathla S, Datta D, Bolat D, Woo E, Duque A, Arellano J, Arnsten Aft, Nairn A C
bioRxiv. 2024 Dec 9:2024.12.05.626721. doi: 10.1101/2024.12.05.626721.
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. Our findings reveal age-related decreases in PDE4 phosphodiesterases that hydrolyze cAMP and increases in calpain-2 and GCPII 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, primes 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病理遵循一种独特的模式，始于内嗅皮质（ERC）并扩散至相互连接的脑区。早期tau病理以可溶性磷酸化tau为特征，由于死后快速去磷酸化，在人类大脑中很难进行研究。恒河猴自然会出现类似于人类AD的与年龄相关的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病理背后的分子过程，重点关注钙和炎症信号通路。我们的研究结果显示，水解cAMP的磷酸二酯酶4（PDE4）随年龄增长而减少，而钙蛋白酶-2和N-乙酰-β-D-氨基葡萄糖苷酶（GCPII）则增加，这些变化与多个表位（pS214-tau、pT181-tau、pT217-tau）的早期tau过度磷酸化同时发生。这些结果表明，从中年开始，ERC中钙信号失调使tau易于过度磷酸化，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。
