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Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces A? and tau pathology in the hippocampus.


ABSTRACT: High levels of the amyloid-beta (A?) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects A?-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)/A? 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/A?, 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/A? accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), A?-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.

SUBMITTER: Rodriguez GA 

PROVIDER: S-EPMC7467290 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus.

Rodriguez Gustavo A GA   Barrett Geoffrey M GM   Duff Karen E KE   Hussaini S Abid SA  

PLoS biology 20200821 8


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 pathologica  ...[more]

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