Abstract
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.
Highlights
We found no indication that the genes encoding INS receptor (INR), IGF-1 receptor (IGF-1R), or glucose transporter 1 (GLUT1) were differentially expressed between late-onset Alzheimer’s disease (LOAD) and Control cells; several genes in the signaling pathways were downregulated in LOAD neural progenitor cells (NPCs) and astrocytes, including IGF-1 and 2, insulin receptor related receptor (INSRR), and insulin receptor substrate 2 (IRS2)
We demonstrate that NPCs and astrocytes as cell populations essential in early CNS development and as key players in mature brain metabolism have numerous bioenergetic and metabolic changes and deficits associated with LOAD (Fig. 5)
We found that compared to NPCs astrocytes had higher respiratory and glycolytic activities and nicotinamide adenine dinucleotide (NAD)/NADH levels but less mitochondrial mass, amino acid metabolism, INSmediated glucose uptake, and IGF-1 and GLUT1 densities than NPCs, demonstrating the acquisition of cell-specific metabolic phenotypes during development
Summary
While many factors underlie the risk and development of LOAD, the “amyloid cascade hypothesis” proposes that an accumulation of beta amyloid along with twisted strands of hyperphosphorylated tau (tangles) are the primary toxic agents in AD [2]. This hypothesis is best supported for familial or early-onset forms of AD (EOAD), less so for LOAD [3, 4]. Unlike EOAD, which is largely determined by single gene variants, LOAD has multiple genetic and environmental risk determinants It is a “multi-hit” disorder, the product of many combined interacting risk factors
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