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

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 overexpress 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 Aβ_1-42 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. Although DIO induced insulin resistance, Aβ_1-42 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 patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 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 AD therapies.