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Journal of Neural Transmission

, Volume 105, Issue 8–9, pp 839–853 | Cite as

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

  • M.-T. Webster
  • B. R. Pearce
  • D. M. Bowen
  • P. T. Francis

Summary.

The mismetabolism of amyloid precursor protein (APP), favouring the production of Aβ, 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 Aβ 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.

Keywords: Alzheimer's disease bradykinin protein kinase C. 

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Copyright information

© Springer-Verlag Wien 1998

Authors and Affiliations

  • M.-T. Webster
    • 1
  • B. R. Pearce
    • 3
  • D. M. Bowen
    • 2
  • P. T. Francis
    • 1
  1. 1.Dementia Research Laboratory, Biochemical Neuropharmacology Group, UMDS,
  2. 2.Department of Neurochemistry, Institute of Neurology, School of Pharmacy, London, United KingdomGB
  3. 3.Department of Pharmacology, School of Pharmacy, London, United KingdomGB

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