| First Author | Hendrix RD | Year | 2021 |
| Journal | Neurobiol Aging | Volume | 97 |
| Pages | 73-88 | PubMed ID | 33161213 |
| Mgi Jnum | J:305383 | Mgi Id | MGI:6709918 |
| Doi | 10.1016/j.neurobiolaging.2020.10.001 | Citation | Hendrix RD, et al. (2021) Alzheimer amyloid-beta- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood. Neurobiol Aging 97:73-88 |
| abstractText | 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-beta peptide (Abeta) 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-Abeta42 line ("Abeta42-tg"), which produces extracellular Abeta1-42 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. Abeta42-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Abeta1-42 accumulation did not, and the impacts of DIO and Abeta on glucose tolerance were merely additive. Abeta42-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 Abeta42-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 Abeta 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. |
