The Role of Human APOE Variants on Microglia Modulation After Early-Life Stress and Predisposition to Earlier Onset of Alzheimer’s Disease

Abstract

The postnatal developmental period is crucial for the shaping and maturation of the brain. Microglia efficiently phagocytose apoptotic cells and synapses during CNS development, resulting in the refinement of neuronal network and synaptic connectivity through elimination of dead cells and excess synapses. Recent studies including those from our laboratory suggest that dysregulation of the brain immune system during development can lead to long-term changes that occur in the adulthood. To understand microglia biology in health and disease, we identified a unique molecular signature of homeostatic microglia (M0). Dysregulation of microglia homeostatic functions may play an important role in the onset and progression of Alzheimer’s disease (AD). We recently identified a role for Apolipoprotein (APOE) signaling in regulation of the microglia neurodegenerative phenotype, which we have termed MGnD. However, it is not known whether microglial APOE ε4 -mediated dysregulation that occurs during early stages of development leads to an increased risk of later developing AD. The premise of our proposal is based on our recently published and preliminary data, which show that microglial phenotype switch from an M0 to an MGnD is triggered by apoptotic neurons via APOE signaling. Moreover, during development there is a peak of APOE signaling at P3. Reciprocal suppression of the APOE and activation of TGFβ signaling is associated with maturation of M0-microglia. Furthermore, APOE ε4 carriers with a traumatic event at childhood, show increased Ab deposits in the adulthood, and have high risk of developing dementia later in life. Early-life stress (ELS) has been proposed to modulate the development and progression of AD and leads in APOE ε4 mice to increased neuronal cell death and cognitive decline during adulthood. Finally, our preliminary data show that ELS induces expression of APOE in microglia and impairs maturation of M0-microglia at P14. Thus, we hypothesize that APOE ε4 impairs the ability of microglia to eliminate dead cells and synapses during the early postnatal period and predisposes to earlier cognitive deficit and Alzheimer’s disease onset.