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Activity-dependent p25 generation regulates synaptic plasticity and Aß-induced cognitive impairment.

Authors: Seo, Jinsoo  Giusti-Rodríguez, Paola  Zhou, Ying  Rudenko, Andrii  Cho, Sukhee  Ota, Kristie T  Park, Christine  Patzke, Holger  Madabhushi, Ram  Pan, Ling  Mungenast, Alison E  Guan, Ji-Song  Delalle, Ivana  Tsai, Li-Huei 
Citation: Seo J, etal., Cell. 2014 Apr 10;157(2):486-498. doi: 10.1016/j.cell.2014.01.065.
Pubmed: (View Article at PubMed) PMID:24725413
DOI: Full-text: DOI:10.1016/j.cell.2014.01.065

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (¿p35KI) to prevent p25 generation. The ¿p35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the ¿p35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of ß-amyloid (Aß)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aß-associated neurotoxicity and AD-like pathology.

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CRRD Object Information
CRRD ID: 13782363
Created: 2018-09-07
Species: All species
Last Modified: 2018-09-07
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.