CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease
Heng-Ye Man; Yuda Huo; Xiu-Lian Wang; Guan Wang; Xiao-Chuan Wang; James Gilbert; Huan Zhou; Qing Zhang; Xiao-Long Feng; Yang-Ping Shentu; Rong Liu; Jukka Westermarck; Jian-Zhi Wang; You-Ming Lu; Zhen-Yu Liuyang
CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease
Heng-Ye Man
Yuda Huo
Xiu-Lian Wang
Guan Wang
Xiao-Chuan Wang
James Gilbert
Huan Zhou
Qing Zhang
Xiao-Long Feng
Yang-Ping Shentu
Rong Liu
Jukka Westermarck
Jian-Zhi Wang
You-Ming Lu
Zhen-Yu Liuyang
CELL PRESS
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042719400
https://urn.fi/URN:NBN:fi-fe2021042719400
Tiivistelmä
Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP beta-cleavage and A beta production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased A beta production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.
Kokoelmat
- Rinnakkaistallenteet [19207]