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Cell. 2014 Apr 10;157(2):486-98. doi: 10.1016/j.cell.2014.01.065.

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

Author information

  • 1The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 2Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
  • 3The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: lhtsai@mit.edu.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24725413
[PubMed - indexed for MEDLINE]
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