High levels of the amyloid-beta (Aβ) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aβ-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aβ accumulation on tauopathy in the entorhinal cortex–hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aβ, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aβ accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer’s disease (AD), Aβ-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.

高水平的淀粉样蛋白-β (Aβ) 肽已被证明会破坏神经元功能并诱导过度兴奋，但尚不清楚 Aβ 相关的过度兴奋可能对 tauopathy 发病机制或体内传播产生何种影响。使用一种新的转基因小鼠系来模拟人类 APP (hAPP)/Aβ 积累对内嗅皮质 - 海马 (EC-HIPP) 网络中 tau 病变的影响，我们证明 hAPP 过表达会加剧 EC-Tau 聚集并加速病理性 tau 扩散到海马体。体内记录显示，hAPP/Aβ（但不是 tau）在 EC 神经元过度活跃和 theta 节律性受损的出现中具有重要作用。EC 神经元过度活跃的慢性化学遗传学衰减导致减少 hAPP/Aβ 积累和减少病理性 tau 扩散到下游海马。