Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology

Abstract

High levels of the amyloid-beta (A{beta}) peptide have been shown to disrupt neuronal function and induce hyperexcitability but it is unclear what effects A{beta}-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of hAPP/A{beta} accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP aggravates EC tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/A{beta}, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chemogenetic attenuation of A{beta}-associated hyperactivity led to reduced hAPP/A{beta} accumulation and reduction of pathological tau in downstream hippocampus. These data strongly support the hypothesis that in Alzheimers disease (AD), A{beta}-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.