1. Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.
- Author
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Goettemoeller AM, Banks E, Kumar P, Olah VJ, McCann KE, South K, Ramelow CC, Eaton A, Duong DM, Seyfried NT, Weinshenker D, Rangaraju S, and Rowan MJM
- Subjects
- Animals, Female, Humans, Male, Mice, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Parvalbumins metabolism, Alzheimer Disease metabolism, Alzheimer Disease genetics, Alzheimer Disease pathology, Alzheimer Disease physiopathology, Amyloid beta-Protein Precursor metabolism, Amyloid beta-Protein Precursor genetics, Entorhinal Cortex metabolism, Entorhinal Cortex pathology, Interneurons metabolism, tau Proteins metabolism, tau Proteins genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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