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

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Goettemoeller, Annie M., Banks, Emmie, Kumar, Prateek, Olah, Viktor J., McCann, Katharine E., South, Kelly, Ramelow, Christina C., Eaton, Anna +5 more·2024·Nature Communications
DOI 10.1038/s41467-024-52297-3PMC PMC11387477

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Abstract

Abstract Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability1. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer’s Disease2-4. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer’s. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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  • These critical regions for memory retention and retrieval are highly vulnerable to Aβ and tau pathology.

    “These critical regions for memory retention and retrieval are highly vulnerable to Aβ and tau pathology25,26,27.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [27]

    The Introduction (page unavailable) identifies the lateral entorhinal cortex as an early site of Alzheimer’s pathology and reports amyloid pathology in its layer II neurons. The Results (page unavailable) also describe it as the first cortical region to develop tau pathology. The paper supports vulnerability of the entorhinal cortex, but these passages do not establish the claim for multiple memory-related regions or address their roles in memory retention and retrieval. (LLM, conf=0.83)

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Authors
Goettemoeller, A. M., Banks, E., Kumar, P., Olah, V. J., McCann, K. E., South, K., Ramelow, C. C., Eaton, A., Duong, D. M., Seyfried, N. T., Weinshenker, D., Rangaraju, S., & Rowan, M. J. M.
Affiliations
  • Emory University (US)
  • Yale University (US)
  • Georgia Institute of Technology (US)
Corresponding author
  • Rangaraju, Srikant
  • Rowan, Matthew J. M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-09-10
Volume
15
Issue
1
Pages
7918-7918
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-52297-3
PMC
PMC11387477
OpenAlex
W4402407137
Cited by
30
References
10
Citations by year
2026: 9 · 2025: 15 · 2024: 6
FWCI
8.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG079269, R21NS133960, F31AG076289, F31AG086006, U01AG061357, RF1AG071587, R01AG075820)
  • Emory University | Alzheimer's Disease Research Center, Emory University (00100569)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS114130)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
entorhinal cortex, Alzheimer's disease, amyloid precursor protein, hyperexcitability, parvalbumin interneurons, tau pathology, regional vulnerability, amyloid-beta, inhibitory interneurons

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