APOE4 reprograms microglial lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications

Area of Science:

• Neuroscience
• Genetics
• Metabolism

Background:

• The apolipoprotein E ε4 (APOE ε4) allele is the primary genetic risk factor for late-onset Alzheimer's disease (AD).
• APOE ε4 significantly impacts brain lipid metabolism, with pronounced effects in microglia, leading to energy deficits and neurodegeneration.

Purpose of the Study:

• To comprehensively review how microglial APOE4-driven lipid metabolic dysregulation exacerbates AD pathology.
• To elucidate the mechanisms underlying APOE4-induced neuroinflammation and impaired microglial function.
• To summarize therapeutic strategies targeting APOE4 in microglia for AD.

Main Methods:

• Literature review synthesizing current research on APOE4, microglial function, and lipid metabolism in AD.
• Analysis of molecular pathways including LilrB3, type I interferon signaling, PU.1/NF-κB, ER stress, and SREBP2.
• Examination of microglial phagocytosis, neuroinflammation, and neuron-microglia interactions.

Main Results:

• Microglial APOE4 disrupts lipid metabolism, causing lipid droplet accumulation, cholesterol overload, and impaired lysosomal function.
• APOE4 activates neuroinflammation via specific signaling pathways and compromises microglial phagocytic capacity for amyloid-β, tau, and synapses.
• Dysregulated lipid metabolism and neuroinflammation driven by microglial APOE4 amplify neurotoxicity and disrupt neuron-microglia communication.

Conclusions:

• Microglial lipid metabolism dysregulation is central to APOE4's role in AD pathogenesis.
• Targeting APOE4-related pathways in microglia, particularly lipid metabolism, presents promising therapeutic opportunities for AD.
• Understanding these mechanisms can guide the development of interventions to protect brain function in AD.