The role of oxidative abnormalities in the pathophysiology of Alzheimer's disease.
Review
Overview
abstract
Several lines of evidence suggest that abnormalities in oxidative metabolism and specifically in mitochondria may play an important role in Alzheimer's disease. Abnormalities of oxidative metabolism exist in this disorder. They have been demonstrated in brain studied in vivo, ex vivo (biopsies), at autopsy, and in non-neural tissues including cultured cells. The abnormalities include a profound deficit in the activity of the ketoglutarate dehydrogenase complex (KGDHC), which is likely to lead to impaired metabolism of glutamate and might contribute to selective neuronal cell death by excitotoxic mechanisms as well as by direct effects on energy metabolism through its role in the tricarboxylic acid cycle. Abnormalities in oxidative metabolism may be related to the pathophysiology of Alzheimer's disease by plausible mechanisms for which there is evidence at least in model systems. Hypoxia is known to induce neuropsychological impairments analogous to those which occur in dementing syndromes. Brain, and specifically neurons, are likely to be particularly vulnerable to impairments of oxidative metabolism because of their demonstrated tight dependence on continuous oxidation of glucose to maintain their structure and function. Neuroanatomic studies as well as recent data from CT, PET, and SPECT scanning agree with formulations that suggest the brain areas of greatest vulnerability in Alzheimer's disease include those particularly sensitive to oxidative impairments. Although the mechanisms of accumulation of the classical neuropathological hallmarks of Alzheimer's disease (paired helical filaments, amyloid plaques) are not known, experimental data suggest that metabolic stresses may contribute to the accumulation of these materials. These data include the accumulation of immunoreactivity of anti-paired helical filament antibodies in cells exposed to a mitochondrial poison, the uncoupler CCCP. Impairments of oxidative metabolism are known to impair the metabolism of neurotransmitters involved in Alzheimer's disease; the synthesis of acetylcholine, which is characteristically involved, is exquisitely sensitive to oxidative abnormalities. Experimental evidence suggests that abnormalities of cellular calcium homeostasis, which have been demonstrated in Alzheimer cells, may mediate key deleterious effects of the abnormalities in oxidative metabolism in this disorder. Experimental studies in animals indicate that age potentiates the effects of inherent oxidative abnormalities on the brain, as does cerebrovascular disease. These observations might help to explain the increasing clinical expression of the gene for Alzheimer's disease with age. They are also in accord with difficulties in separating the role of vascular from that of inherent degenerative factors in dementia of later onset. Treatment with L-carnitine, a manipulation designed to mitigate consequences of a mitochondrial abnormality, normalized several non-mitochondrial abnormalities in cultured Alzheimer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
