Datta Dibyadeep, Arnsten Amy F T
Department of Psychiatry, Yale Medical School, New Haven, Connecticut, USA.
Department of Neuroscience, Yale Medical School, New Haven, Connecticut, USA.
Alzheimers Dement. 2025 Feb;21(2):e14477. doi: 10.1002/alz.14477. Epub 2025 Jan 8.
Aging rhesus macaques provide a unique model for learning how age and inflammation drive early-stage pathology in sporadic Alzheimer's disease, and for testing potential therapeutics. Unlike mice, aging macaques have extensive association cortices and inflammatory signaling similar to humans, are apolipoprotein E ε4 homozygotes, and naturally develop tau and amyloid pathology with marked cognitive deficits. Importantly, monkeys provide the unique opportunity to study early-stage, soluble hyperphosphorylated tau (p-tau), including p-tau217. As soluble p-tau is rapidly dephosphorylated post mortem, it is not captured in human brains except with biopsy material. However, new macaque data show that soluble p-tau is toxic to neurons and capable of seeding across cortical circuits. Extensive evidence indicates that age-related inflammatory signaling contributes to calcium dysregulation, which drives tau hyperphosphorylation and amyloid beta generation. Pharmacological studies in aged macaques suggest that inhibiting inflammation and restoring calcium regulation can reduce tau hyperphosphorylation with minimal side effects, appropriate for potential preventive therapeutics. HIGHLIGHTS: Aging monkeys provide a unique window into early stage, soluble phosphorylated tau (p-tau). Inflammation with advancing age leads to calcium dysregulation, p-tau, and amyloid beta (Aβ). Macaque research shows p-tau undergoes transsynaptic seeding early in the cortex. p-tau traps amyloid precursor protein-containing endosomes, which may increase Aβ and drive vicious cycles. Restoring calcium regulation in cortex reduced p-tau217 levels in aged macaques.
衰老的恒河猴为研究年龄和炎症如何驱动散发性阿尔茨海默病的早期病理过程以及测试潜在治疗方法提供了一个独特的模型。与小鼠不同，衰老的猕猴具有与人类相似的广泛联合皮质和炎症信号，是载脂蛋白Eε4纯合子，并且自然会出现tau蛋白和淀粉样蛋白病理变化以及明显的认知缺陷。重要的是，猴子提供了研究早期可溶性高磷酸化tau蛋白（p-tau）的独特机会，包括p-tau217。由于可溶性p-tau在死后会迅速去磷酸化，除了活检材料外，它不会在人类大脑中被捕获。然而，新的猕猴数据表明，可溶性p-tau对神经元有毒性，并且能够在皮质回路中播种。大量证据表明，与年龄相关的炎症信号会导致钙调节异常，从而驱动tau蛋白过度磷酸化和β淀粉样蛋白生成。对老年猕猴的药理学研究表明，抑制炎症并恢复钙调节可以减少tau蛋白过度磷酸化，且副作用最小，适合作为潜在的预防性治疗方法。要点：衰老的猴子为早期可溶性磷酸化tau蛋白（p-tau）提供了一个独特的窗口。随着年龄增长的炎症会导致钙调节异常、p-tau和β淀粉样蛋白（Aβ）。猕猴研究表明p-tau在皮质早期经历跨突触播种。p-tau捕获含有淀粉样前体蛋白的内体，这可能会增加Aβ并驱动恶性循环。恢复皮质中的钙调节可降低老年猕猴的p-tau217水平。
