Amyloid Beta Regulates Astrocytic Glucose Metabolism and Insulin Signaling in Experimental Models of Alzheimer’s Disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by amyloid beta (Aβ) plaques, neuroinflammation and cognitive impairment. Metabolic disturbances, particularly brain insulin resistance, are increasingly recognized as central features of AD pathophysiology. Astrocytes, essential for brain energy metabolism, exhibit a loss of homeostatic functions in AD, possibly promoting neurodegeneration. Even though the main astrocytic glucose transporters are non-insulin dependent, insulin may regulate astroglial glucose metabolism. Our objective was to evaluate insulin signaling and astrocyte metabolism in the PDAPP-J20 transgenic mouse model of familial AD and in mouse primary astrocyte cultures exposed to Aβ. Adult PDAPP-J20 mice showed hyperinsulinemia, hippocampal insulin resistance and astrocytic proinflammatory activation. The reactive glial phenotype was accompanied by decreased insulin receptor levels in this chronic setting. Exposure of primary astrocytes to Aβ induced proinflammatory activation, oxidative stress and loss of glutamate transporter EAAT2, crucial for neuroprotection. Even though Aβ-exposed astrocytes showed increased insulin receptor levels in this acute setting, insulin-induced phosphorylation of the receptor was hampered. Amyloid-treated astrocytes also showed increased glucose uptake, lactate release and glycogen storage. Insulin treatment was associated with a recovery of mitochondrial membrane potential and increased amyloid uptake, highlighting a pro-homeostatic role for the hormone. Our results highlight the interplay between insulin signaling and astrocyte metabolism at different experimental and temporal settings of amyloid pathology. Understanding these mechanisms may help to design therapeutic strategies aimed at restoring metabolic balance and mitigating neurodegeneration.