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Cell DOI:10.1016/j.cell.2014.01.065

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

Publication TypeJournal Article
Year of Publication2014
AuthorsSeo, J, Giusti-Rodríguez, P, Zhou, Y, Rudenko, A, Cho, S, Ota, KT, Park, C, Patzke, H, Madabhushi, R, Pan, L, Mungenast, AE, Guan, J-S, Delalle, I, Tsai, L-H
JournalCell
Volume157
Issue2
Pages486-98
Date Published2014 Apr 10
ISSN1097-4172
KeywordsAdaptor Proteins, Signal Transducing, Alzheimer Disease, Amyloid beta-Peptides, Animals, Calpain, Cell Cycle Proteins, Cognition, Cyclin-Dependent Kinase 5, Disease Models, Animal, Dopamine and cAMP-Regulated Phosphoprotein 32, Endocytosis, Gene Knock-In Techniques, Hippocampus, Humans, Long-Term Potentiation, Long-Term Synaptic Depression, Mice, Nerve Tissue Proteins, Phosphotransferases, Receptors, N-Methyl-D-Aspartate, Synapses
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)00213-X
DOI10.1016/j.cell.2014.01.065
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24725413?dopt=Abstract

Alternate JournalCell
PubMed ID24725413
PubMed Central IDPMC4327772
Grant ListF31 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