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The Journal of Neuroscience, October 11, 2006, 26(41):10536-10541; doi:10.1523/JNEUROSCI.3133-06.2006

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Brief Communications
p25/Cyclin-Dependent Kinase 5 Induces Production and Intraneuronal Accumulation of Amyloid In Vivo

Jonathan C. Cruz,^1 * Dohoon Kim,^1 * Lily Y. Moy,¹ Matthew M. Dobbin,¹ Xiaoyan Sun,² Roderick T. Bronson,³ and Li-Huei Tsai¹

¹Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, and ²Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, and ³Rodent Histopathology Core, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Li-Huei Tsai at her present address: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Boston, MA 02139. Email: lhtsai{at}mit.edu

Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid (A) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of A 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, A peptide generation, and intraneuronal A 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 A levels before any evidence of neuropathology in these mice. Intracellular A accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or -site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the A 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.

Key words: Alzheimer's disease; amyloid ; BACE1; cdk5; neurodegeneration; p25

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Received Oct. 15, 2005; accepted Sept. 6, 2006.

Correspondence should be addressed to Li-Huei Tsai at her present address: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Boston, MA 02139. Email: lhtsai{at}mit.edu

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