The role of innate immune genes in Alzheimer's disease

Abstract

Purpose of review: The aim of this study was to provide an update on the role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease, with an emphasis on microglial receptors CD33 and TREM2.

Recent findings: Genome-wide association studies (GWAS) have identified many Alzheimer's disease risk genes related to immune response and microglia including the phagocytic receptors CD33 and TREM2. Recent GWAS and pathway analyses emphasize the crucial role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease. Disease-associated microglia have been characterized by TREM2-dependent upregulation of phagocytic and lipid metabolism genes. Impaired microglial phagocytosis results in amyloid beta (Aβ) accumulation leading to neuroinflammation that is the primary cause of neurodegeneration. CD33 and TREM2 modulate neuroinflammation in Alzheimer's disease and have emerged as therapeutic targets in Alzheimer's disease. Progress has been made to inhibit CD33 by gene therapy, small molecules or immunotherapy, and to increase TREM2 activity by immunotherapy. Finally, mAbs against CD33 and TREM2 have entered clinical trials and may reduce neuroinflammation in Alzheimer's disease brain.

Summary: Targeting neuroinflammation via CD33 inhibition and/or TREM2 activation may have important implications for neurodegeneration in Alzheimer's disease and may be an addition to monoclonal anti-Aβ antibody treatments that remove plaques without reducing neuroinflammation.

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FIGURE 1

The protective allele of the CD33 SNP rs3865444 is associated with reductions in both CD33 expression and insoluble Aβ42 levels in Alzheimer's disease brain. The minor allele of the CD33 SNP rs3865444, which confers protection against Alzheimer's disease, leads to reductions in both CD33 expression and amyloid burden in human Alzheimer's disease brain (right). Microglial cells expressing high levels of CD33 are limited in their capacity to uptake and clear Aβ; the result is high levels of Aβ that accumulate in the brain (left).

FIGURE 2

Working model of crosstalk between the microglial receptors CD33 and TREM2. Phosphorylation of full-length CD33 on ITIM domains leads to recruitment of SHP1 and SHP2 phosphatases and inhibitory signaling. Recruitment of SYK to DAP12, the adaptor of TREM2, leads to intracellular signaling that promotes phagocytosis and chemotaxis. CD33-ΔV-Ig may represent a loss-of-function or gain-of-function isoform.