Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight

Abstract

Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system (CNS) is separated from the blood circulation by the blood-brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.

Figure1 |. Roles of neuroinflammation in different stages of Alzheimer’s disease

a | At an early stage disease prior to or just following the initiation of plaque deposition, NLRP3 inflammasome activation by pathological changes results in release of ASC specks from microglia that promote amyloid-β seeding. Activated microglia may capture amyloid-β seeds via TREM2-amyloid-β interaction and boost plaque formation by generating local high concentrations of ASC specks around amyloid-β seeds to facilitate amyloid-β aggregation for plaque core initiation. b | In the mid-stage disease when plaques accumulate, microglia cluster around plaques in a TREM2-dependent fashion and trim amyloid-β fibrils on the edge to compact the plaque. Plaque-associated microglia also serve as a barrier between the plaque and surrounding tissues to reduce amyloid-β-induced toxicity to neurites. TREM2 deficiency hinders full activation of DAM/MGnD microglia and significantly reduces the number of plaque-associated microglia. This results in enlarged amyloid-β plaques with wispy fibre-like structures projecting from loosely packed cores and greater neuritic dystrophy in close vicinity. c | In the late-stage disease, tau pathology accumulates. Microglia may accelerate tau pathology spreading by taking in extracellular tau and subsequently releasing certain tau species. Activated microglia also secret IL-1β that signals on neurons and likely indirectly through astrocytes as well to enhance neuronal tau phosphorylation by activating tau kinases. d | Along with tau pathology buildup, neurodegeneration occurs. DAM/MGnD microglia appear to exacerbate neuronal loss. Activated microglia induce A1 astrocytes, which kill/damage neurons via secreting neurotoxic factors and loss of neurotrophic functions. The large amounts of ROS/NO generated during microglia activation can also directly injure/kill neurons. With increased neuronal death, DAM/MGnD microglia are engaged in removing neuron corpses. However, they can also target stressed-but-viable neurons that present ‘eat-me’ signals for phagoptosis, causing more neuronal loss.

Figure 2:. Model of immunomodulatory functions of ApoE in Alzheimer’s disease pathogenesis and neurodegeneration along disease progression

a | ApoE exacerbates amyloid-β pathology during the initial amyloid-β seeding stage. This is likely partially due to a direct pro-aggregating effect of ApoE on amyloid-β through ApoE-amyloid-β interactions. In addition, ApoE may serve as an opsonin bridging microglia with amyloid-β seeds by binding to TREM2 on microglia. This may result in recruitment of more activated microglia to amyloid-β seeds that promote plaque formation via secreting ASC specks or other mechanisms. b | During the plaque accumulation phase, DAM/MGnD microglia clustering around amyloid-β plaques for plaque trimming and insulation is strictly regulated by ApoE. ApoE is required for full DAM/MGnD microglial activation that allows them to associate with plaques. In addition, ApoE is abundantly present in amyloid plaques and may promote DAM/MGnD microglia to target plaques via ApoE-TREM2 interaction. c | In the late-stage disease when intracellular pathological tau accumulation and other factors result in more neuronal injury and death, ApoE may accumulate on the cell surface of jeopardized neurons likely due to their impaired cellular uptake function, and may opsonize these neurons for phagoptosis by DAM/MGnD microglia via interaction with TREM2, thus exacerbating neurodegeneration. In addition, ApoE is required for full DAM/MGnD microglial polarization. Fully activated DAM/MGnD microglia in the presence of ApoE may further aggravate neuronal death by elevating oxidative stress, enhancing A1 astrocytic activation and exacerbating tau pathology.