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CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease
Yang-Ping Shentu1, Yuda Huo2, Xiao-Long Feng1
1Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
Cancerous Inhibitor of PP2A (CIP2A) overexpression drives Alzheimer's disease (AD) pathology by inhibiting Protein Phosphatase 2A (PP2A). This leads to cognitive deficits and synaptic degeneration, suggesting CIP2A as a therapeutic target for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Protein phosphatase 2A (PP2A) activity is crucial for neuronal health, and its inhibition is implicated in Alzheimer's disease (AD) pathogenesis.
- The precise mechanisms causing PP2A downregulation in AD brains are not fully understood.
Purpose of the Study:
- To investigate the role of Cancerous Inhibitor of PP2A (CIP2A) in AD pathogenesis.
- To elucidate the molecular mechanisms linking CIP2A to tau and amyloid precursor protein (APP) pathology.
Main Methods:
- Western blotting and immunohistochemistry to assess CIP2A and PP2A levels in AD brains.
- In vitro assays to determine the effect of CIP2A on tau and APP phosphorylation.
- Viral vector-mediated delivery of CIP2A in mouse hippocampus to assess cognitive and synaptic function.
- Analysis of Aβ production and its feedback effect on CIP2A expression.
Main Results:
- CIP2A is significantly overexpressed in AD brains, correlating with reduced PP2A activity.
- CIP2A overexpression leads to hyperphosphorylation of tau and APP, increased APP β-cleavage, and elevated Aβ production.
- CIP2A induces tau mislocalization, synaptic degeneration, and AD-like cognitive deficits and impaired long-term potentiation in mice.
- Aβ production was found to exacerbate CIP2A expression, indicating a detrimental feedback loop.
Conclusions:
- CIP2A overexpression is a key driver of PP2A inhibition and subsequent AD-related pathologies, including tau/APP hyperphosphorylation and neurodegeneration.
- CIP2A contributes to cognitive decline and synaptic dysfunction observed in Alzheimer's disease.
- Targeting CIP2A presents a promising therapeutic strategy for Alzheimer's disease treatment.