Microglia and its Genetics in Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid- beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in terms of both pathogenesis and progression. As the main innate immune cell type in the central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions, including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complex etiology of AD and provide new insight into the unmet need for effective treatment.

Keywords: AD risk genes; APOE; Alzheimer's Disease; GWAS.; microglia; neuroinflammation.

Figure 1.. Microglia subtypes and activation process

Microglia can be activated from homeostatic status (M0) to activate forms (M1 or M2), which can be further categorized into different subtypes. After activation, PAM expresses abundant of IL-1β and shows characteristic gene profile changes. Increased intracellular Ca²⁺ contributes to its hyperreactive immune response. DAM can be activated by various damaged-associated molecular patterns (DAMPs), which impair the phagocytosis and proteostasis functions. Dark Microglia can be activated by aging, chronic stress, AD pathologies or CX₃CR1 deficiency. TREM2 is increasingly expressed in dark microglia near Aβ plaques. While the M2 subtypes, including M2a, M2b and M2c, in general are anti-inflammatory and promote proteostasis and repair. The inflammatory cytokines and neurotoxic factors produced by activated M1 microglia lead to neuro damage, which can stimulate more Aβ plaques made by neuron and go back to activate microglia further. Abbreviations: IL-1β: interleukin-1β; Aβ: β-amyloid; sAβ: soluble β-amyloid; PAM: Plaque-associated microglia; DAM: Disease-associated microglia.

Figure 2.. AD risk genes and signaling pathways in microglia

As a triggering receptor expressed on myeloid cells, TREM2 have various ligands from extracellular, including Aβ, LDL, HDL, apoptotic cells and ApoE. The combination of TREM2 and its ligand can phosphorylate ITAM of DAP12, then triggering SYK, PI3K/Akt and GSK3β downstream signaling. The interaction between APOE and TREM2 triggers the transcription regulation and microglia dysfunction. Microglia speck-like protein containing a CARD (ASC) and Capase-1 upregulate proinflammation cytokines IL-1β and IL-18. In the presence of sialic-acid, CD33 inhibits the TREM-dependent uptake of Aβ. LY294002, an inhibitor of PI3K/Akt pathway; Abi3 variants is associated with Aβ or tau aggregation in microglia and ABI3 may combine with CYFIP1 and WAVE2 to form wave regulator complex (WRC) and regulate microglia activation in AD. PLCγ2 can be phosphorylated by SYK and stimulate IP3, which then triggering Ca²⁺ signaling, modulating phagocytosis of microglia or activating NF-κB pathway. Abbreviations: Aβ: β-amyloid; LDL: low density lipoprotein; HDL: high density lipoprotein; MDA-LDL: malondialdehyde-modified LDL; DAP12: DNAX-activating protein; IL-1β: interleukin-1β; IL-18: interleukin-18.