Astrocyte β-catenin suppression by HIV and methamphetamine drives senescence and dysfunction of MEGF10-dependent phagocytosis, neuronal support, and BBB integrity.

内容摘要

Astrocytes are essential regulators of central nervous system (CNS) homeostasis, and their dysfunction can amplify neuroinflammation and neurodegeneration. HIV and methamphetamine (Meth) are known to downregulate β-catenin signaling and induce astrocyte senescence, but whether this senescent state is functionally pathogenic and contributes directly to neuroinflammatory processes remains unclear. Here, we investigated how senescent astrocytes respond across prototypical astrocytic functions.In vitro, human iPSC-derived astrocytes infected with HIV and/or exposed to Meth developed a senescence phenotype (increased p16INK4A) accompanied by reduced expression of the phagocytic receptor MEGF10 and impaired engulfment of apoptotic neurons. HIV/Meth exposure also shifted astrocyte secretomes toward proinflammatory profiles (IL-6, CCL2, CXCL1, and ICAM-1), and astrocyte-conditioned media decreased neuronal PSD95 and NFL and disrupted endothelial adherens and tight junction proteins (VE-cadherin, occludin, claudin-5), resulting in increased monocyte transmigration. Mechanistically, pharmacologic activation or lentiviral expression of active β-catenin protected astrocytes from senescence, preserving MEGF10 expression and phagocytic capacity under HIV/Meth exposure, while MEGF10 overexpression independently restored phagocytosis. In a human-mouse chimera model (NSG mice xenotransplanted with human iPSC-derived astrocytes), HIV infection and/or Meth administration increased p16INK4A and reduced MEGF10 expression in engrafted human astrocytes, recapitulating in vitro findings.Together, these studies demonstrate that HIV and Meth suppress β-catenin signaling to drive a functionally disruptive astrocyte senescence program linked to impaired MEGF10-dependent phagocytosis, diminished neuronal support, and compromised blood-brain barrier integrity. Restoring β-catenin signaling and preserving MEGF10 function emerge as rational strategies to prevent astrocyte-driven neuroinflammation and neuropathogenesis in HIV/Meth co-morbidity.