Abstract
Evidence accumulated over the past three decades suggests that the neurons that degenerate in Alzheimer's disease (AD) suffer metabolic compromise, hyperexcitability and consequent calcium ion (Ca2+) overload-mediated dysfunction and death. Contributing to the neuronal network hyperexcitability in AD is the degeneration of inhibitory GABAergic interneurons, apparently as a result of their unusually high firing frequency and metabolic demand. Aging, genetic factors, and unhealthy lifestyles including lack of exercise and overconsumption of calorie-rich foods may compromise the ability of neurons to sustain mitochondrial function and to remove damaged molecules. Here I briefly review evidence supporting a role for early GABAergic neuron degeneration and consequent neuronal network hyperexcitability in AD. I then highlight data suggesting pivotal roles for ketones, NAD+ and the mitochondrial protein deacetylase sirtuin 3 (SIRT3) in protecting against hyperexcitability in AD.
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