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

• Published in: PLoS biology 2020-08, Vol.18 (8), p.e3000851-e3000851
• Main Authors: Rodriguez, Gustavo A, Barrett, Geoffrey M, Duff, Karen E, Hussaini, S Abid
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Age; Aging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Attenuation; Bioaccumulation; Biology; Biology and Life Sciences; Brain research; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cognitive ability; Computer and Information Sciences; Cortex (entorhinal); Dependovirus - genetics; Dependovirus - metabolism; Disease Models, Animal; Electrodes, Implanted; Engineering and Technology; Entorhinal Cortex - metabolism; Entorhinal Cortex - pathology; Female; Funding; Gene Expression Regulation; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Humans; Hyperactivity; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Pathogenesis; Pathology; Phosphorylation; Protein Aggregates; Proteins; Research and Analysis Methods; Stereotaxic Techniques; Supervision; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - pathology; Tauopathies - therapy; Theta Rhythm - physiology; Transduction, Genetic; Transgenes; Transgenic animals; Transgenic mice; β-Amyloid
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000851

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.