Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology
Annie M Goettemoeller, Emmie Banks, Prateek Kumar, Viktor Janos Oláh, Katharine E McCann, Kelly South, Christina C. Ramelow, Anna Eaton, Duc M. Duong, Nicholas T. Seyfried, David Weinshenker, Srikant Rangaraju, Matthew JM Rowan
Abstract
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. In this study using an adult-onset mouse model of Alzheimer’s pathology, we uncovered a neuron-type-specific mechanism responsible for region-specific circuit dysfunction. Short-term expression of human amyloid precursor protein (hAPP) led to hyperexcitability in the entorhinal cortex, but not in isocortex, due to a distinct vulnerability of PV interneurons in the entorhinal region.