CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease

Cell Reports
Yangping ShentuRong Liu

Abstract

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 β-cleavage and Aβ 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 Aβ 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.

Citations

Feb 26, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Hui WeiRong Liu
Jan 2, 2020·International Journal of Molecular Sciences·Tao ZhangTae Ho Lee
Oct 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ying ZhouYangping Shentu
Nov 4, 2020·European Journal of Medicinal Chemistry·Lisha WangBengt Winblad
Mar 27, 2020·Saudi Journal of Biological Sciences·Richard L JayarajRami Beiram
Feb 1, 2021·Journal of Molecular Modeling·Pragya KushwahaShafiul Haque
Apr 6, 2021·ACS Chemical Neuroscience·Yiming PanJuan Kong
Apr 6, 2021·Current Research in Immunology·Mohd Moin KhanRiitta Lahesmaa
Jul 13, 2021·Frontiers in Molecular Neuroscience·Xiaomin YinWei Qian
Jul 10, 2021·Biochemical Society Transactions·Iris VerbinnenVeerle Janssens
Apr 28, 2019·Neuroscience Letters·Nima N NaseriWenjie Luo

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Methods Mentioned

BETA
transgenic
co-immunoprecipitation
CoIP
fluorescence microscopy
transfection
immunoprecipitation assay
Infrared Imaging
ELISA

Software Mentioned

GraphPad Prism
GraphPad
ImageJ

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