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

PLoS Biol. 2020 Aug 21;18(8):e3000851. doi: 10.1371/journal.pbio.3000851. eCollection 2020 Aug.

Abstract

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 pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aβ, 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/Aβ accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aβ-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Electrodes, Implanted
  • Entorhinal Cortex / metabolism*
  • Entorhinal Cortex / pathology
  • Female
  • Gene Expression Regulation
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism
  • Neurons / pathology
  • Protein Aggregates
  • Stereotaxic Techniques
  • Tauopathies / genetics*
  • Tauopathies / metabolism
  • Tauopathies / pathology
  • Tauopathies / therapy
  • Theta Rhythm / physiology
  • Transduction, Genetic
  • Transgenes
  • tau Proteins / genetics*
  • tau Proteins / metabolism

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Protein Aggregates
  • tau Proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2