Cortical region confers neuron-type-specific vulnerability to human APP expression

Alzheimer’s Disease is a devastating and an irreversible neurodegenerative disease currently afflicting 50 million individuals worldwide, a number expected to escalate three-fold over the next 25 years. Preventative treatment is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, the earliest observed pathophysiological correlate to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the cortical region first impacted by Alzheimer’s Disease. The origin of hyperexcitability in early stage-disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific APP in a model of sporadic Alzheimer’s Disease. Shockingly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, prior to changes in surrounding excitatory neurons. This study suggests early disease interventions addressing non-excitatory cell-types may protect regions first vulnerable to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.