Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling

Authors

• Ravichandra S. Davargaon, University of Kentucky College of Medicine
• Nirmal Verma, University of KentuckyFollow
• Deepak Kotiya, University of Kentucky College of MedicineFollow
• Noah Leibold, University of Kentucky College of Medicine
• Gopal Viswanathan Velmurugan, University of Kentucky
• Han Coburn, University of Kentucky College of Medicine
• Kuey C. Chen, University of KentuckyFollow
• Daniel Ruiz, Emory University
• Victor Corces, Emory University
• Huazhen Liu, University of KentuckyFollow
• Pradeep Kachroo, University of KentuckyFollow
• Pankaj K. Singh, University of Florida
• Matthew S. Gentry, University of KentuckyFollow
• Sanda Despa, University of KentuckyFollow
• Florin Despa, University of KentuckyFollow

Abstract

Brain glucose dysregulation is shared by Alzheimer's disease (AD) and diabetes, but whether it arises from central or peripheral mechanisms remains unclear. Amylin, a pancreatic hormone, normally supports CNS cAMP-PKA signaling, metabolism and memory; however, prediabetes-associated hypersecretion disrupts this balance. Using human amylin-inducible mice, we show that toggling amylin secretion during metabolic stress bidirectionally regulates brain glycolysis and function. Excess amylin overactivates cAMP-PKA signaling, suppressing glycolysis and inducing Tau-Ser214 phosphorylation, two core features of AD pathology. This state is accompanied by activation of the amino acid starvation response, Tau-T231 hyperphosphorylation, pTau-Aβ coupling, neuroinflammation and memory deficit. In contrast, reducing amylin in prediabetes preserves glycolysis, ATF4-dependent proteostasis and cognition. Astrocytes emerge as primary targets, as amylin receptor blockade prevents glycolytic deficits ex vivo, and amylin accumulates in GFAP-enriched regions in vivo. Together, these results define prediabetic hyperamylinemia as an upstream, modifiable driver of PKA-mediated tau pathology linking metabolic dysfunction to AD.

Document Type

Article

Publication Date

3-20-2026

Notes/Citation Information

Publisher Copyright: © 2026 The Author(s)

Digital Object Identifier (DOI)

10.1016/j.isci.2026.115157

Archival?

Archival

Repository Citation

Davargaon, Ravichandra S.; Verma, Nirmal; Kotiya, Deepak; Leibold, Noah; Velmurugan, Gopal Viswanathan; Coburn, Han; Chen, Kuey C.; Ruiz, Daniel; Corces, Victor; Liu, Huazhen; Kachroo, Pradeep; Singh, Pankaj K.; Gentry, Matthew S.; Despa, Sanda; and Despa, Florin, "Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling" (2026). Neurology Faculty Publications. 149.
https://uknowledge.uky.edu/neurology_facpub/149