Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Annie M. Goettemoeller, Emmie Banks, Prateek Kumar, Viktor J. Olah, Katharine E. McCann, Kelly South, Christina C. Ramelow, Anna Eaton, Duc M. Duong, Nicholas T. Seyfried, David Weinshenker, Srikant Rangaraju () and Matthew J. M. Rowan ()
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Annie M. Goettemoeller: Emory University School of Medicine
Emmie Banks: Emory University School of Medicine
Prateek Kumar: Yale University
Viktor J. Olah: Emory University School of Medicine
Katharine E. McCann: Emory University School of Medicine
Kelly South: Emory University School of Medicine
Christina C. Ramelow: Emory University
Anna Eaton: Georgia Institute of Technology
Duc M. Duong: Emory University School of Medicine
Nicholas T. Seyfried: Emory University School of Medicine
David Weinshenker: Emory University School of Medicine
Srikant Rangaraju: Yale University
Matthew J. M. Rowan: Emory University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Preventative treatment for Alzheimer’s Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.

Date: 2024
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DOI: 10.1038/s41467-024-52297-3

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