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AAV9-mediated Cdk5 inhibitory peptide(CIP) reverses pathological changes and behavioral deficits in the Alzheimer's disease model mice

Yong He  Suyue Pan  Miaojing Xu  Rongni He  Wei Huang  Pingping Song  Jianou Huang  Han-Ting Zhang  Yafang Hu  
【摘要】:Cdk5, binding to and activated by p35, phosphorylates multiple substrates and plays an essential role in the development and function of the central neuron system. However, proteolytic production of p25 from p35 under stress conditions leads to inappropriate activation of Cdk5 and contributes to hyperphosphorylation of tau and other substrates related to the pathogenesis of Alzheimer's disease(AD). Selective inhibition of aberrant Cdk5 activity via genetic overexpression of Cdk5 inhibitory peptide(CIP) reduces pathological changes and prevents brain atrophy and memory loss in p25-transgenic mice. In the present study, we delivered AAV9-GFP-CIP into brain cells via intracerebroventricular infusion in APP/PSEN1 double transgenic mice at 3-month-old, after the occurrence of β amyloid(Aβ) aggregation and hyperphosphorylation of tau. Three months treatment of AAV9-GFP-CIP reduced pathological changes including tau hyperphosphorylation, Aβ deposit, astrocytosis and microgliosis, which were correlated with the reversal of memory loss and anxiety-like behavior observed in APP/PS1 mice. Neuroprotection effect of AAV9-GFP-CIP lasted to additional seven months, which was the endpoint of the study. These findings provide a novel strategy to selectively targeting Cdk5 for treatment of AD.

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