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

NEUROBIOLOGY OF AGING

卷:97

Article

Hendrix, Rachel D.^1,6  Ou, Yang²  Davis, Jakeira E.³  Odle, Angela K.¹  Groves, Thomas R.^1,7  Allen, Antino R.^1,4  Childs, Gwen V.¹  Barger, Steven W.^1,2,5 

[1] Dept Neurobiol & Dev Sci, Little Rock, AR USA

[2] Dept Geriatr, Little Rock, AR USA

[3] Grad Program Interdisciplinary Biomed Sci, Little Rock, AR USA

[4] Univ Arkansas Med Sci, Dept Pharmaceut Sci, Little Rock, AR 72205 USA

[5] Cent Arkansas Vet Healthcare Syst, Geriatr Res Educ & Clin Ctr, Little Rock, AR USA

[6] Washington Univ, Dept Neurol, St Louis, MO 63110 USA

[7] Axiom Huntsworth Hlth, Yardley, PA USA

关键词: Alzheimer's disease;    Amyloid beta-peptide;    Astrocytes;    Diabetes mellitus;    Type 2;    Glucose;    Glucose transporter type 1;    Obesity;   

DOI  :  10.1016/j.neurobiolaging.2020.10.001

来源: Elsevier

【 摘 要 】

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 (A beta) 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-A beta(42) line (A beta(42)-tg), which produces extracellular A beta(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. A beta(42)-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, A beta(1-42) accumulation did not, and the impacts of DIO and A beta on glucose tolerance were merely additive. A beta(42)-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 A beta(42)-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 A beta 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. Published by Elsevier Inc.

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