INHIBITION OF ENERGY-METABOLISM ALTERS THE PROCESSING OF AMYLOID PRECURSOR PROTEIN AND INDUCES A POTENTIALLY AMYLOIDOGENIC DERIVATIVE

The cellular mechanisms which lead to the generation and pathological deposition of beta amyloid in Alzheimer's disease are unknown. In this report we describe the proteolytic processing of the amyloid precurso r protein (APP) to an 11.5-kDa COOH-terminal derivative which contains the full-length beta amyloid sequence. This processing step normally occurs at low levels in parallel with APP maturation in the secretory pathway. Inhibition of oxidative energy metabolism by sodium azide or the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone i ncreased the proteolysis of APP to the 11.5-kDa derivative by about 80 -fold with accumulation of this APP derivative in the Gels complex. Ag ents which inhibit protein transport in the secretory pathway, includi ng monensin and brefeldin A, also increased the production of the 11.5 -kDa derivative. Inhibition of APP maturation demonstrated that the 11 .5-kDa derivative could be produced by proteolysis of immature APP. Th ese results demonstrate that APP processing to potentially amyloidogen ic COOH-terminal derivatives occurs in either the endoplasmic reticulu m or Golgi complex and can be modulated by the state of cellular energ y metabolism. Deficits in oxidative energy metabolism have recently be en found in the cerebral cortex of patients with Alzheimer's disease. These findings raise the possibility that energy-related metabolic str ess may lead to altered metabolism of APP and contribute to amyloidosi s in Alzheimer's disease.