Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: A novel excitoprotective mechanism involving modulation of tau phosphorylation

Ping Han, Fei Dou, Feng Li, Xue Zhang, Yun Wu Zhang, Hui Zheng, Stuart A. Lipton, Huaxi Xu, Francesca-Fang Liao

Research output: Contribution to journalArticle

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Abstract

Alzheimer's disease is cytopathologically characterized by loss of synapses and neurons, neuritic amyloid plaques consisting of β-amyloid (Aβ) peptides, and neurofibrillary tangles consisting of hyperphosphorylated tau protein in susceptible brain regions. Aβ, which triggers a cascade of pathogenic events including tau phosphorylation and neuronal excitotoxicity, is proteolytically derived from β-amyloid precursor protein (APP); the pathological and physiological functions of APP, however, remain undefined. Here we demonstrate that the level of tau phosphorylation in cells and brains deficient in APP is significantly higher than that in wild-type controls, resulting from activation of cyclin-dependent kinase 5 (CDK5) but not glycogen synthase kinase 3, the two major tau kinases. In addition, we show that overexpression of APP or its non-amyloidogenic homolog amyloid precursor-like protein 1 suppresses both basal and stress-induced CDK5 activation. The ectodomain of APP, sAPPα, is responsible for inhibiting CDK5 activation. Furthermore, neurons derived from APP-deficient mice exhibit reduced metabolism and survival rates and are more susceptible to excitotoxic glutamateinduced apoptosis. These neurons also manifest significant defects in neurite outgrowth compared with neurons from the wild-type littermates. The observed neuronal excitotoxicity/apoptosis is mediated through a mechanism involving CDK5 activation. Our study defines a novel neuroprotective function for APP in preventing tau hyperphosphorylation via suppressing overactivation of CDK5. We suggest that CDK5 activation, through a calcium/calpain/p25 pathway, plays a key role in neuronal excitotoxicity and represents an underlying mechanism for the physiological functions of APP.

Original languageEnglish (US)
Pages (from-to)11542-11552
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number50
DOIs
StatePublished - Dec 14 2005

Fingerprint

Cyclin-Dependent Kinase 5
Serum Amyloid A Protein
Amyloid beta-Protein Precursor
Phosphorylation
Neurons
Amyloid Plaques
Apoptosis
Glycogen Synthase Kinase 3
tau Proteins
Neurofibrillary Tangles
Calpain
Brain
Amyloid
Synapses
Alzheimer Disease
Phosphotransferases
Calcium

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein : A novel excitoprotective mechanism involving modulation of tau phosphorylation. / Han, Ping; Dou, Fei; Li, Feng; Zhang, Xue; Zhang, Yun Wu; Zheng, Hui; Lipton, Stuart A.; Xu, Huaxi; Liao, Francesca-Fang.

In: Journal of Neuroscience, Vol. 25, No. 50, 14.12.2005, p. 11542-11552.

Research output: Contribution to journalArticle

Han, Ping ; Dou, Fei ; Li, Feng ; Zhang, Xue ; Zhang, Yun Wu ; Zheng, Hui ; Lipton, Stuart A. ; Xu, Huaxi ; Liao, Francesca-Fang. / Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein : A novel excitoprotective mechanism involving modulation of tau phosphorylation. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 50. pp. 11542-11552.
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