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

Cell
Authors
Keywords
Abstract

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 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of β-amyloid (Aβ)-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 Aβ-associated neurotoxicity and AD-like pathology.

Year of Publication
2014
Journal
Cell
Volume
157
Issue
2
Pages
486-98
Date Published
2014 Apr 10
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.01.065
PubMed ID
24725413
PubMed Central ID
PMC4327772
Links
Grant list
F31 GM080055 / GM / NIGMS NIH HHS / United States
R01 NS051874 / NS / NINDS NIH HHS / United States
F31GM80055-03 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States