Preventative treatment for Alzheimer’s Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.

阿尔茨海默病 (AD) 的预防性治疗十分严峻，但早期区域脆弱性的潜在机制仍不清楚。在 AD 中，与认知能力下降最早的病理生理学关联之一是过度兴奋，这首先在内嗅皮层中观察到。为什么过度兴奋优先出现在 AD 的特定区域尚不清楚。利用野生型小鼠的区域细胞类型特异性蛋白质组学和电生理学，我们发现了内嗅皮层对人类淀粉样前体蛋白（hAPP）的独特敏感性。内嗅过度兴奋是由于小白蛋白（PV）中间神经元相对于周围兴奋性神经元的选择性脆弱性造成的。这种效应被含有人源化β淀粉样蛋白序列的APP嵌合体部分复制。 EC 过度兴奋性可以通过人 Tau 与 hAPP 共表达（以增加病理性 tau 种类为代价）或通过增强体内 PV 中间神经元兴奋性来改善。这项研究表明，针对抑制性神经元的早期干预可能会保护脆弱区域免受 APP/淀粉样蛋白和 tau 病理学的影响。