THE EFFECTS OF PERTURBED ENERGY-METABOLISM ON THE PROCESSING OF AMYLOID PRECURSOR PROTEIN IN PC12 CELLS

The mismetabolism of amyloid precursor protein (APP), favouring the pr oduction of A beta, is considered to be central to the pathogenesis of Alzheimer's disease (AD). However it remains to be established whethe r the causative factor is the reported toxicity of A beta or reduced p roduction of secretory derivatives of APP which may have trophic or ne uroprotective properties. One possible contributory factor to an imbal ance in APP metabolism is the impaired cellular energy availability de scribed 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 perturbe d cells with the lysosomotropic agent chloroquine restored intracellul ar 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 str ess may lead to altered metabolism of APP-like proteins favouring a po tentially amyloidogenic pathway. Furthermore, the observation that act ivation of PKC is able to overcome this potentially pathogenic process has important implications for treatment of AD with the current gener ation of cholinomimetic drugs, suggesting that such drugs may slow dis ease progression as well as improve cognitive dysfunction.