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Elevated p16Ink4a Expression Enhances Tau Phosphorylation in Neurons Differentiated From Human-Induced Pluripotent
Kristopher Holloway1, Kashfia Neherin1, Yingduo Song2
1Department of Pediatrics, 3 NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Aging Cell
|January 6, 2025
Summary
The cyclin-dependent kinase inhibitor p16Ink4a (p16) exacerbates Alzheimer's disease (AD) pathology by increasing tau phosphorylation in neurons. This suggests a positive feedback loop between p16 and tau, contributing to AD progression.
Area of Science:
- Neuroscience
- Cell Biology
- Aging Research
Background:
- Increased p16Ink4a (p16) expression is observed in Alzheimer's disease (AD) brains and during normal aging.
- Eliminating p16-expressing cells in AD mouse models reduces tau pathology and improves cognition, but p16's role in AD pathogenesis is unclear.
Purpose of the Study:
- To investigate whether inducing p16 expression in neurons exacerbates AD pathologies.
- To elucidate the mechanisms by which p16 influences AD pathogenesis.
Main Methods:
- Developed a doxycycline-inducible system to control p16 up-regulation in human induced pluripotent stem cells (iPSCs) and differentiated neurons.
- Analyzed changes in cell proliferation, cell cycle genes, and signaling pathways (focal adhesion, interferon α response, PI3K-Akt) in iPSCs.
- Assessed tau phosphorylation and amyloid beta secretion in differentiated cortical neurons upon p16 induction.
Main Results:
- Induced p16 expression in iPSCs reduced proliferation and altered gene expression.
- In differentiated neurons, p16 up-regulation increased tau phosphorylation (Ser202/Thr205, Thr231) in a cell-autonomous manner.
- Amyloid beta secretion remained unaffected by p16 up-regulation.
Conclusions:
- p16 plays a critical role in regulating tau phosphorylation in neurons, contributing to AD pathological progression.
- A positive feedback loop between p16 and tau may exacerbate tau pathologies in AD.
