Astrocytes, a subset of glial cells named for their star-shaped appearance, are the most abundant cell type in the central nervous system (CNS). Astrocytes play a highly neuroprotective role in the brain by providing neuronal maintenance and support, notably at the blood-brain barrier. Astrocytes also participate in synaptic transmission and neuroinflammatory responses, and serve as the brain’s main source of the apolipoprotein ApoE and cholesterol, which, exported via the ABCA1 transporter, is critical to membrane integrity. Normally, astrocytes aid in Aβ clearance through ApoE production, which positively facilitates Aβ clearance by excretion across the blood brain barrier, or astrocytic uptake through either phagocytosis or receptor-mediated endocytosis, where LRP1 has been well studied. Aβ bound to ApoE and high-density lipoproteins can also be cleared through microglial uptake or microglial-mediated neuroinflammatory responses. Mutations to the APOE gene are critically associated with late-onset Alzheimer’s disease; in this context, it is thought that altered ApoE function leads to extracellular Aβ aggregation and compromised integrity of neuronal membranes, which in turn prompts a neuroinflammatory response that further dysregulates the system. Despite its well-established association with the majority of non-familial AD cases, the mechanistic underpinnings of the pathogenic role of ApoE remain unclear.
