Interconnections of Insulin/Igf-1 Signaling and Autophagy Abnormalities in Alzheimer’s Disease

Authors

• Wang Liao
• Jinfeng Xuan
• Woo-In Ryu
• Mariana K Bormann
• Yoon Lee
• Haley Dion
• Elizabeth Evangelista
• Ruiyi Li
• Lucas Trambaiolli
• Jun Liu
• Arthur J Siegel
• Brent P Forester
• Bruce M Cohen
• Kai-Christian Sonntag

Language

English

Publication Date

7-1-2025

Journal

Alzheimer's & Dementia Journal

DOI

10.1002/alz.70099

PMID

40613332

PMCID

PMC12231206

PubMedCentral® Posted Date

7-4-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Introduction: Impaired insulin (INS) and insulin-like growth factor 1 (IGF-1) signaling are features of both brain aging and late-onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause-and-effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood.

Methods: We investigated INS/IGF-1 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals.

Results: Compared to control old-age cells, protein levels in the INS/IGF-1 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS/IGF-1/AKT/FOXO1 or mTOR axes and associated endo- and autophagic processes were largely intact in old-age but disrupted in LOAD fibroblasts.

Discussion: Our results suggest that reduced AKT activation, in the context of altered INS/IGF-1 signaling, and connected alterations of endocytosis and autophagy are features of LOAD pathology but not aging, per se.

Highlights: Levels of insulin/insulin-like growth factor 1 (INS/IGF-1) factors in late-onset Alzheimer's disease (LOAD) cells are higher than in healthy old controls. AKT activation by INS/IGF-1 signaling is specifically diminished in LOAD cells. INS/IGF-1/AKT/forkhead box protein O1/mechanistic target of rapamycin kinase related endocytosis/autophagy are disrupted in LOAD cells. Intracellular endocytic/autophagic structure distribution is altered in LOAD cells. INS/IGF-1 reverses endocytic/autophagic processes in LOAD versus old control cells.

Keywords

Humans, Alzheimer Disease, Insulin-Like Growth Factor I, Autophagy, Signal Transduction, Insulin, Aged, Male, Fibroblasts, Female, Proto-Oncogene Proteins c-akt, Aged, 80 and over, TOR Serine-Threonine Kinases, Aging, Cells, Cultured, Forkhead Box Protein O1, Middle Aged, Adult, AKT, autophagy, endocytosis, forkhead box protein O1, insulin, insulin‐like growth factor 1, late‐onset Alzheimer's disease, mechanistic target of rapamycin kinase, skin fibroblasts, starvation

Published Open-Access

yes

Recommended Citation

Liao, Wang; Xuan, Jinfeng; Ryu, Woo-In; et al., "Interconnections of Insulin/Igf-1 Signaling and Autophagy Abnormalities in Alzheimer’s Disease" (2025). Faculty, Staff and Student Publications. 4459.
https://digitalcommons.library.tmc.edu/uthmed_docs/4459