Altered metabolic function induced by amyloid-beta oligomers and PSEN1-mutations in iPSC-derived astrocytes.

Abstract

Altered energy metabolism in Alzheimers disease (AD) is considered a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are increasingly implicated in multiple neurodegenerative diseases. We report that astrocytes differentiated from early onset familial Alzheimers disease (fAD) patients or control cells treated with Amyloid {beta} oligomers exhibit significant changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism. Furthermore, we demonstrate evidence of gliosis in fAD astrocytes in addition to a change in metabolic pathways including glutamate, purines, arginine, and the citric acid cycle. Homeostatic responses to brain activity and cellular metabolism are central to normal brain function. However, altered brain metabolism and cellular stress present significant risk factors for the onset and progression of neurodegenerative disease. This study demonstrates that fAD derived astrocytes present multiple metabolic and disease associated phenotypes early in their development suggesting that chronic alterations in fAD patient early in life that present significant risk factors for disease progression in mid-life and suggest key targets for potential diagnostic features and therapeutic agents late onset dementia in midlife.