Losing Power: Declines in Mitochondrial Respiratory Capacity in Alzheimer's Disease

Marked decreases in cerebral cortical glucose utilization, as revealed by 2-FDG PET scans, are emerging as a reliable biomarker for the development of mild cognitive impairment (MCI) and Alzheimer's disease (AD), which currently affects over 20 million people worldwide. The amyloid cascade hypothesis posits that the majority of AD pathogenesis, including reductions in bioenergy, is the result of the increased production and aggregation of A1-42 , a cleavage product of amyloid precursor protein. We studied the acute effects of aggregated A1-42 on O 2 consumption (respiration) in neuroblastoma cells and mitochondria isolated from non-AD mouse and human brain, as well as the effects of reducing A1-42 in a neuroblastoma-based cell line shown to overproduce A1- 42 and recapitulate many AD-related pathologies. We also studied O 2 consumption in mitochondrial isolates from CTL and AD frontal cortex. Our findings show that A1-42 peptide is not a likely cause of the bioenergetic deficits in AD brain because brain levels of A1-42 did not correlate with reduced O 2 consumption in AD frontal cortex, did not acutely inhibit O 2 consumption when in an aggregated state, or lead to reversal of bioenergetic impairments when reduced. Instead, we observed absolute levels of mitochondrial mass to be reduced in AD frontal cortex, which correlates with reduced O 2 consumption. We also observed reductions in expression of genes responsible for mitobiogenesis, metabolic regulation, and antioxidant scavenging, suggesting the observed reduction in mitochondrial mass may be the result of altered signaling for increasing mitochondrial mass to meet cellular demands. Additionally, decreased antioxidant responses would threaten neuronal function by allowing the buildup of toxic III reactive oxygen species. Our findings also demonstrated a potential mitotoxicity for Areducing agents, specifically -secretase inhibitors, suggesting we should proceed with caution when studying their therapeutic efficacy in human subjects. Finally, our observations suggest altering the progression of AD will require a correction of mitobiogenesis and restoration of antioxidant production.

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