How the TREM2-APOE Pathway Shapes Dysfunctional Brain Immune Cells in Neurodegenerative Diseases

A specific apolipoprotein E (APOE)-dependent molecular signature was identified in microglia from models of neurodegenerative disorders.

• Microglia lose their normal homeostatic function during neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD).
• The transition to a neurodegenerative microglial phenotype is mediated by the APOE pathway after the uptake of dying neurons.
• TREM2 signaling is involved in inducing APOE signaling within microglia.
• Targeting the TREM2-APOE pathway may help restore the normal function of microglia in ALS and AD models and protect against neuronal loss.
• APOE-mediated neurodegenerative microglia appear to have lost their ability to maintain immune tolerance.

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