Brain cells derived from Alzheimer's disease patients have multiple specific innate abnormalities in energy metabolism

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer's disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a multi-hit disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Automated summary

The study found that neural progenitor cells and astrocytes differentiated from induced pluripotent stem cells of late-onset Alzheimer's disease patients exhibit multiple inter-related bioenergetic alterations, including changes in mitochondrial respiration, reduced levels of NAD/NADH, and diminished glucose uptake. These findings suggest that Alzheimer's disease may involve multiple hits and innate inefficient cellular energy management.