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 overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line (“Aβ 42 -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. Aβ 42 -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. Aβ 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 Aβ 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 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.

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

“…ApoE4-TR mice trended toward an impairment, and this prevented the apparent elevation by Aβ from reaching significance. As we had observed earlier in mice with a wild-type Apoe locus (Hendrix et al, 2020), glucose tolerance in females expressing either of the human ApoE variants was unaffected by Aβ accumulation (Fig. 1B).…”

Impacto de dietas obesogênicas em aspectos comportamentais e em biomarcadores preditivos de doença de Alzheimer: uma revisão de literatura

“…Assim como em dietas ricas em gordura, as dietas com alto teor de sacarose podem desencadear déficits de memória espacial dos animais (camundongos) em estudo (Yeh et al, 2020). Adicionalmente, camundongos com excesso de beta-amiloide apresentam diminuição na taxa metabólica cerebral de consumo da glicose (CMRglc), da mesma forma que em pacientes com a Doença de Alzheimer (Hendrix et al, 2021). Dessa maneira, os estudos analisados conseguiram evidenciar que, independente do modelo de dieta obesogênica empregada, a obesidade resultante é um fator que pode colaborar com a progressão e surgimento da Doença de Alzheimer em modelo animal.…”

“…Atualmente, postula-se que a obesidade seja um fator de risco para o desenvolvimento da DA, devido aos aspectos que envolvem principalmente a resistência à insulina que contribui com os processos neurodegenerativos; a atenuação da sinalização da leptina; o aumento nos níveis aumentados de peptídeo beta-amiloide (Aβ); o aumento da neuroinflamação e a redução da taxa metabólica cerebral de consumo de glicose (do inglês cerebral metabolic rate of glucose consumption -CMRglc) (Martelli, 2013;Hendrix et al, 2021).…”

Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease

“…Further, Aβ accumulation is associated with the decrease in membrane expression of the glucose transporter GLUT1 (Winkler et al, 2015), and microvascular endothelial cells are more susceptible to Aβ toxicity under hyperglycemic conditions, suggesting that hyperglycemia is also a risk factor for vascular damage associated with AD (Carvalho et al, 2014). Indeed, AD and type 2 diabetes patients with hyperglycemia have lower glucose uptake by the brain (Hendrix et al, 2021). This suggests that the brain's glucose supply is altered during neurodegenerative events and that other mechanisms such as the action of AGEs could be involved in the cognitive impairment observed in these patients.…”