The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells

Webster, M-T., Pearce, B.R., Bowen, D.M. and Francis, P.T. (1998) The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells. Journal of Neural Transmission, 105 (8-9). pp. 839-853.

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The mismetabolism of amyloid precursor protein (APP), favouring the production of A beta, is considered to be central to the pathogenesis of Alzheimer's disease (AD). However it remains to be established whether the causative factor is the reported toxicity of A beta or reduced production of secretory derivatives of APP which may have trophic or neuroprotective properties. One possible contributory factor to an imbalance in APP metabolism is the impaired cellular energy availability described in AD. The aim of this study was to investigate processing of APP-like proteins following inhibition of oxidative energy metabolism in PC12 cells. Under these conditions, intracellular and secreted APP-like proteins were significantly reduced. Treatment of energy perturbed cells with the lysosomotropic agent chloroquine restored intracellular concentrations of APP-like proteins to the control range, while the secretion was completely restored by activation of protein kinase C. These findings raise the possibility that energy related metabolic stress may lead to altered metabolism of APP-like proteins favouring a potentially amyloidogenic pathway. Furthermore, the observation that activation of PKC is able to overcome this potentially pathogenic process has important implications for treatment of AD with the current generation of cholinomimetic drugs, suggesting that such drugs may slow disease progression as well as improve cognitive dysfunction.

Item Type:Article
Uncontrolled Keywords:Alzheimer's disease - bradykinin - protein kinase C.
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2419
Journal or Publication Title:Journal of Neural Transmission
Deposited By:Library Staff
Deposited On:10 Nov 2011 09:57
Last Modified:10 Nov 2011 09:57

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