α-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease

摘要

The heroin analogue 1-methyl-4-phenylpyridinium, MPP+. both in vitfo and in vivo. produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase mul- tienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly. a fragment of amyloid protein, Ap,-'z, is lethal to hippocampal cells, producing recent memory deficits characteristic of Aizheimer's disease. Here we show that addition of 4 mM D-p-hydroxybutyrate protected cultured mesen- cephalic neurons from MPP+ toxicity and hippocampal neurons from Ap1--42 toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mito- chondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.