MAP kinase signaling cascade dysfunction specific to Alzheimer's disease in fibroblasts

Wei Qin Zhao, Lakshmi Ravindranath, Ali S. Mohamed, Ofer Zohar, Gina H. Chen, Constantine G. Lyketsos, René Etcheberrigaray, Daniel L. Alkon

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Abstract

Mitogen-activated protein kinases (such as Erk1/2) regulate phosphorylation of the microtubule-associated protein tau and processing of the amyloid protein β, both events critical to the pathophysiology of Alzheimer's disease (AD). Here we report that enhanced and prolonged Erk1/2 phosphorylation in response to bradykinin (BK) was detected in fibroblasts of both familial and sporadic AD, but not age-matched controls (AC). The AD-associated abnormality in Erk1/2 phosphorylation was not seen in fibroblasts from Huntington's disease patients with dementia. The elevation of Erk1/2 phosphorylation occurred immediately after BK stimulation and required an IP3-sensitive Ca2+ release as well as activation of PKC and c-src as upstream events. Treatment of cells with the PI-3 kinase blocker LY924002 partially inhibited the BK-stimulated Erk1/2 phosphorylation in AC, but had no effect in AD cells, suggesting that the BK-induced Erk1/2 phosphorylation in AD cells is independent of PI-3 kinase. Activation of the cAMP-responsive element binding protein (CREB) monitored as an increase in phosphorylation at Ser-133 was also observed after BK stimulation. Unlike the AD-specific differences for Erk1/2, however, the BK-stimulated CREB phosphorylation was not different between AC and AD cells. Abnormal Erk1/2 activities may alter downstream cellular processes such as gene transcription, amyloid precursor protein processing, and tau protein phosphorylation, which contribute to the pathogenesis of AD. Moreover, detection of AD-specific differences in MAP kinase in peripheral tissues may provide an efficient means for early diagnosis of AD as well as help us to identify therapeutic targets for drug discovery.

Original languageEnglish (US)
Pages (from-to)166-183
Number of pages18
JournalNeurobiology of Disease
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2002

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ASJC Scopus subject areas

  • Neurology

Cite this

Zhao, W. Q., Ravindranath, L., Mohamed, A. S., Zohar, O., Chen, G. H., Lyketsos, C. G., Etcheberrigaray, R., & Alkon, D. L. (2002). MAP kinase signaling cascade dysfunction specific to Alzheimer's disease in fibroblasts. Neurobiology of Disease, 11(1), 166-183. https://doi.org/10.1006/nbdi.2002.0520