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AAIC 2022 | What contributes to hyperexcitability in Alzheimer’s disease?

Neuronal network hyperexcitability is thought to be an early event in Alzheimer’s disease pathogenesis, with recent research indicating it may represent a predictive marker of cognitive dysfunction. In both preclinical models and living patients, activity recordings from single neurons, networks, or whole brain regions show higher frequency, lower threshold firing. The exact mechanisms causing neuronal excitability changes are not fully characterized, but several contributing events have been uncovered. Mark Mattson, PhD, Johns Hopkins University School of Medicine, Baltimore, MD, sheds light on the key role of mitochondrial dysfunction in aberrant neuronal excitability. Impaired ATP generation and accumulation of dysfunctional mitochondria due to impaired mitophagy are thought to contribute to the hyperexcitability seen in AD. Additionally, changes in glutamate transport are thought to lead to excitability changes. While the data is mixed regarding what happens to glutamate levels, several studies have shown enhanced glutamatergic signaling, attributable to reduced astrocytic uptake, reduced levels of glutamine synthetase, and/or increased vesicular glutamate transporter expression. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.