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Attenuation of Aβ-associated hyperactivity reduces Aβ and tau pathology along the entorhinal cortex-hippocampal network

View ORCID ProfileGustavo A Rodriguez, Geoffrey M Barrett, View ORCID ProfileKaren E Duff, View ORCID ProfileS Abid Hussaini
doi: https://doi.org/10.1101/487405
Gustavo A Rodriguez
1Taub Institute for Research on Alzheimer ’s disease and the Aging Brain, Columbia, University Medical Center, New York, NY 10032, USA
2Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
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Geoffrey M Barrett
1Taub Institute for Research on Alzheimer ’s disease and the Aging Brain, Columbia, University Medical Center, New York, NY 10032, USA
2Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
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Karen E Duff
1Taub Institute for Research on Alzheimer ’s disease and the Aging Brain, Columbia, University Medical Center, New York, NY 10032, USA
2Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
3Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
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  • For correspondence: sah2149@cumc.columbia.edu ked2115@cumc.columbia.edu
S Abid Hussaini
1Taub Institute for Research on Alzheimer ’s disease and the Aging Brain, Columbia, University Medical Center, New York, NY 10032, USA
2Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
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  • For correspondence: sah2149@cumc.columbia.edu ked2115@cumc.columbia.edu
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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 hAPP/Aβ 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/Aβ, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chemogenetic attenuation of Aβ-associated hyperactivity led to reduced hAPP/Aβ accumulation and reduction of pathological tau in 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.

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Posted December 04, 2018.
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Attenuation of Aβ-associated hyperactivity reduces Aβ and tau pathology along the entorhinal cortex-hippocampal network
Gustavo A Rodriguez, Geoffrey M Barrett, Karen E Duff, S Abid Hussaini
bioRxiv 487405; doi: https://doi.org/10.1101/487405
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Attenuation of Aβ-associated hyperactivity reduces Aβ and tau pathology along the entorhinal cortex-hippocampal network
Gustavo A Rodriguez, Geoffrey M Barrett, Karen E Duff, S Abid Hussaini
bioRxiv 487405; doi: https://doi.org/10.1101/487405

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