p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo.
Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid beta (Abeta) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of Abeta 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, Abeta peptide generation, and intraneuronal Abeta 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 Abeta levels before any evidence of neuropathology in these mice. Intracellular Abeta accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or beta-site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the Abeta 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.
Cruz
Jonathan C
JC
Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Kim
Dohoon
D
Moy
Lily Y
LY
Dobbin
Matthew M
MM
Sun
Xiaoyan
X
Bronson
Roderick T
RT
Tsai
Li-Huei
LH
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D010770:Phosphotransferases / Q000502:physiology
D016229:Amyloid beta-Peptides; C492236:Cdk5r1 protein, mouse; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5