AMYLOID-Β–INDUCED ASTROCYTIC INSULIN RESISTANCE AND METABOLIC REPROGRAMMING IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia. Beyond amyloid beta (Aβ) and tau aggregation, inflammation and insulin resistance are also frequent in AD brains. Astrocytes are crucial in maintaining homeostasis and managing inflammatory responses. This study aimed to examine the metabolic and inflammatory status of PDAPP-J20 transgenic (TG) mice, an AD model, and assess inflammatory activation, energy metabolism, and insulin signaling in astrocytes in vitro after Aβ exposure. We hypothesized that Aβ-treated astrocytes adopt a proinflammatory phenotype and lose homeostatic functions. Our findings revealed impaired insulin signaling (pAkt/Akt) in the hippocampus, along with reduced hippocampal insulin receptor (IR) levels. Immunolabeling for IR showed a decrease in GFAP+ astrocytes, which also displayed increased GFAP and S100b labeling, indicating proinflammatory reactivity. In vitro, Aβ exposure led to increased NFkB nuclear translocation, elevated S100b, and decreased EAAT2 expression. Western blot and immunofluorescence analysis showed higher IR expression and increased membrane localization in Aβ-exposed astrocytes. However, insulin-prompted IR phosphorylation decreased and Akt phosphorylation remained unchanged after Aβ exposure. Aβ-exposed astrocytes also showed increased glucose uptake and a trend towards higher lactate production and glycogen accumulation. Additionally, the number of mitochondria decreased, while superoxide production increased. Despite reduced lipid droplet density, their colocalization with mitochondria increased, suggesting a metabolic shift towards β-oxidation. These results suggest that hippocampal insulin resistance and glial reactivity are concurrent in experimental AD. Aβ-exposed astrocytes adopt a proinflammatory phenotype with impaired insulin signaling and mitochondrial dysfunction, providing insight into AD pathophysiology.