Molecular Biology of Brain Aging and Disease

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Molecular indices of synaptic integrity and energy metabolism were quantified in autopsy samples of cerebral cortex from healthy humans of different ages, and from patients with Alzheimer disease (AD). Significant age declines were found in synaptic proteins involved in remodeling of pre- and postsynaptic (dendritic) elements. AD had an additional 81% decrease in the level of drebrin, a protein regulating postsynaptic plasticity. AD also was associated with reduced activity and gene expression of mitochondrial and nuclear enzymes involved in oxidative phosphorylation, the process by which energy is produced in the form of ATP. Other evidence including positron emission (PET) suggests that, in the early stages of AD, these reductions represent reversible "downregulation" of brain oxidative phosphorylation. Mitochondrial DNA (mtDNA) transcription was shown, using an isolated mitochondrial transcription system from rat liver mitochondria, to be stimulated by ADP but not ATP, and to be abolished by the respiratory inhibitor, rotenone. Thus, mitochondrial transcription is regulated by cellular energy demands and is coupled with respiration. An extract of Ginkgo biloba, EGb 761, is reported to be therapeutic in AD. PC12 cells were exposed to different concentrations of this extract for up to 72 h. Northern blot analysis demonstrated increased levels of the mitochondrial-encoded NADH dehydrogenase subunit 1 (ND1), suggesting that EGb 761 can upregulate mitochondrial oxidative phosphorylation. Aluminum has been implicated in several neurological disorders, particularly dialysis dementia. PC12 cells exposed to aluminum had reduced mRNA for the cytochrome oxidase subunit III (COXIII) at 1 umol, a concentration reported in brains of dialysis dementia patients. The aluminum effect was reversible. Levels of mitochondrially coded ND1 mRNA and 12S rRNA and nuclear encoded b-actin were unaffected, suggesting selective targeting of COX by aluminum.