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

Summary: 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. : PP2A inactivation plays a key role in AD pathogenesis. Shentu et al. report that endogenous PP2A inhibitor CIP2A is upregulated in AD brains. CIP2A overexpression promotes β-cleavage of APP and tau hyperphosphorylation through PP2A inhibition, leading to impairments in synapse, hippocampal LTP, and memory. Keywords: CIP2A, PP2A, tau/APP hyperphosphorylation, synaptic degeneration, memory deficits, Alzheimer’s disease