Genetics ignite focus on microglial inflammation in Alzheimer's disease

Abstract

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD.

Fig. 1

Several interactions have been reported between the AD risk genes involved in inflammation. TREM2 signals through the ITAM of DAP12 to activate microglial phagocytosis; however, TREM2 expression has also been shown to dampen pro-inflammatory cytokine production activated by TLRs. Activated CD33 recruits SHP-1 and SHP-2 to inhibit Syk signaling; CD33 has also been shown to antagonize CD14/TLR4 signaling. Sialylated apoE, which complexes with Aβ, may serve as a CD33 ligand. ApoE appears to dampen TLR4 and TLR2 signaling and inhibit induction of pro-inflammatory cytokines. SHIP1 antagonizes PI3K action by converting PIP3 to PIP2; SHIP1 has also been shown to bind to and antagonize TREM2 /DAP12 signaling in osteoclasts. SHIP1 also complexes with CD2AP, another AD-implicated protein, to inhibit Syk ubiquitination and degradation. CR1 is a C3b/C4b receptor that promotes phagocytosis; complement components have been shown to complex with Aβ. ABCA7 has been localized to phagocytic cups and linked to Aβ clearance, although its mechanism of action is currently unknown. Proteins encoded by genes associated with AD risk by genetics are shown with solid outlines; proteins that mediate these interactions are shown with dashed outlines

Fig. 2

Microglial activation can be neuroprotective and/or neurotoxic; the actions of AD risk proteins modulate these effects. The normal actions of CD33 and SHIP1 (encoded by INPP5D) appear to antagonize both forms of microglial activation, while CR1 action appears to promote both Aβ phagocytosis and the production of neurotoxic pro-inflammatory cytokines such as TNF. TREM2 appears to promote phagocytosis while dampening pro-inflammatory cytokine production. ABCA7 helps to mediate phagocytosis. APOE2 and APOE3 are anti-inflammatory, while APOE4 promotes inflammation and neurotoxicity