p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo

Jonathan C. Cruz, Dohoon Kim, Lily Y. Moy, Matthew M. Dobbin, Xiaoyan Sun, Roderick T. Bronson, Li Huei Tsai

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid β (Aβ) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of Aβ are well outlined; however, there is a relative dearth of knowledge pertaining to signaling pathways and molecular mechanisms that can modulate this process. Here, we demonstrate a novel role for p25/cyclin-dependent kinase 5 (Cdk5) in regulating APP processing, Aβ peptide generation, and intraneuronal Aβ accumulation in inducible p25 transgenic and compound PD-APP transgenic mouse models that demonstrate deregulated Cdk5 activity and a neurodegenerative phenotype. Induction of p25 resulted in enhanced forebrain Aβ levels before any evidence of neuropathology in these mice. Intracellular Aβ accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or β-site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the Aβ accumulation caused by p25/Cdk5 deregulation. Collectively, these findings delineate a novel pathological mechanism involving aberrant APP processing by p25/Cdk5 and have important implications in AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)10536-10541
Number of pages6
JournalJournal of Neuroscience
Volume26
Issue number41
DOIs
StatePublished - Oct 11 2006
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Amyloid beta-Protein Precursor
Amyloid
Prosencephalon
Alzheimer Disease
Peptides
Axonal Transport
Transgenic Mice
Axons
Phenotype
Enzymes
Proteins

Keywords

  • Alzheimer's disease
  • Amyloid β
  • BACE1
  • Cdk5
  • Neurodegeneration
  • p25

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo. / Cruz, Jonathan C.; Kim, Dohoon; Moy, Lily Y.; Dobbin, Matthew M.; Sun, Xiaoyan; Bronson, Roderick T.; Tsai, Li Huei.

In: Journal of Neuroscience, Vol. 26, No. 41, 11.10.2006, p. 10536-10541.

Research output: Contribution to journalArticle

Cruz, Jonathan C. ; Kim, Dohoon ; Moy, Lily Y. ; Dobbin, Matthew M. ; Sun, Xiaoyan ; Bronson, Roderick T. ; Tsai, Li Huei. / p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 41. pp. 10536-10541.
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