Divergent CNS –Peripheral Signaling Reflects Astrocyte Dysfunction and Contributes to Insulin Resistance in Early Aβ Pathology

ABSTRACT Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are age‐related disorders with similar pathological features, particularly insulin resistance and chronic inflammation. However, the primary drivers of insulin resistance in the AD brain remain debated. Although astrocytes and their metabolic functions have been increasingly implicated in AD, their specific role in brain insulin resistance is still unclear. In this study, we excluded peripheral metabolic confounders and focused on the alterations during a narrow time window surrounding amyloid‐β (Aβ) plaque deposition in J20 mice. As Aβ pathology progressed, we observed a reduction in astrocyte numbers with increased morphological complexity. Furthermore, transcriptomic profiling demonstrated altered gene expression at synaptic, glial, and metabolic levels, along with a general suppression of insulin signaling pathways that indicated insulin resistance. Notably, we found a significant downregulation of serum and glucocorticoid‐inducible kinase 1 (SGK1) and upregulation of insulin receptor substrate 2 (IRS2) expression, which diverged from the classic pattern observed in peripheral insulin resistance. We also detected a contradictory cytokine pattern in T‐helper 17, where interleukin (IL)‐6 and IL‐17 levels were decreased in the hippocampus but elevated in the serum. This opposing trajectory suggests that astrocyte dysfunction and SGK1 downregulation have a critical role in immune signaling imbalance. Taken together, these findings highlight astrocyte depletion and/or dysfunction as key drivers of brain‐specific insulin resistance and immune dysregulation in early AD, and that metabolic impairments in AD have a central nervous system‐specific nature distinct from that in T2DM.