Alzheimer amyloid β-peptide disrupts membrane localization of glucose transporter 1 in astrocytes: Implications for glucose levels in brain and blood

Abstract Alzheimer’s disease (AD) is associated with disturbances in blood glucose regulation, and Type-2 diabetes elevates the risk for dementia. A role for amyloid β-peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that over-express mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line (“Aβ42-tg”), which produces extracellular Aβ1-42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose (“western”) diet. Aβ42-tg mice were impaired in both spatial memory and glucose tolerance. Though DIO induced insulin resistance, Aβ1-42 accumulation did not; and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ42-tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ42-tg mice had reduced glucose utilization, similar to human AD patients. This was associated with insufficient trafficking of glucose transporter 1 (GLUT1) to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower CMRglc and diminished function of parenchymal GLUT1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of Alzheimer’s disease therapies.