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ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Cellular and Molecular Mechanisms of Brain-aging
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1549770
Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation
Provisionally accepted
Shveta Bathla1,2
Dibyadeep Datta2
Dinara Bolat3
Elizabeth Woo3
Alvaro Duque3
Jon I Arellano3
Amy F T Arnsten3
Angus Clark Nairn2*- 1Yale University, New Haven, United States
- 2Department of Psychiatry,School of Medicine, Yale University, New Haven, Connecticut, United States
- 3Department of Neuroscience, School of Medicine, Yale University, New Haven, Connecticut, United States
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Tau pathology in sporadic Alzheimer's disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation. Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways. Our findings reveal an age-related decrease in PDE4 phosphodiesterase that hydrolyzes cAMP and increases in calpain-2 and glutamate carboxypeptidase II that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau). These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, may prime tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.
Keywords: Entorhinal Cortex, tau pathology, cAMP-calcium signaling, Alzheimer's disease, calpain-2, GCPII, PDE4 phosphodiesterase calcium dysregulation, Inflammation
Received: 21 Dec 2024; Accepted: 07 Apr 2025.
Copyright: © 2025 Bathla, Datta, Bolat, Woo, Duque, Arellano, Arnsten and Nairn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Angus Clark Nairn, Department of Psychiatry,School of Medicine, Yale University, New Haven, 06510, Connecticut, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.