Elsevier

Current Opinion in Neurobiology

Volume 36, February 2016, Pages 74-81
Current Opinion in Neurobiology

Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease

https://doi.org/10.1016/j.conb.2015.10.004Get rights and content

Highlights

  • Microglia are the immune cells of the CNS.

  • Microglial reactivity has been implicated in the pathogenesis of Alzheimer's disease.

  • We know considerably more about the genetic link between early-onset AD than late-onset AD.

  • Recent GWAS have highlighted gene mutations linked to enhanced risk of LOAD, and which code for proteins expressed in microglia.

  • This review discusses these recent findings and the implications for microglial reactivity in AD.

Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD), and microglia, the brain's resident phagocyte, are pivotal for the immune response observed in AD. Microglia act as sentinel and protective cells, but may become inappropriately reactive in AD to drive neuropathology. Recent Genome Wide Association Studies (GWAS) have identified more than 20 gene variants associated with an increased risk of late-onset AD (LOAD), the most prevalent form of AD [1]. The findings strongly implicate genes related to the immune response (CR1, CD33, MS4A, CLU, ABCA7, EPHA1 and HLA-DRB5-HLA-DRB1), endocytosis (BIN1, PICALM, CD2AP, EPHA1 and SORL1) and lipid biology (CLU, ABCA7 and SORL1) [2, 3, 4, 5, 6, 7, 8], and many encode proteins which are highly expressed in microglia [1]. Furthermore, recent identification of a low frequency mutation in the gene encoding the triggering receptor expressed in myeloid cells 2 protein (TREM2) confers increased risk of AD in LOAD cohorts with an effect size similar to that for APOE, until recently the only identified genetic risk factor associated with LOAD [9, 10••] (Figure 1). The present review summarises our current understanding of the probable roles of microglial genes in the regulation of neuroinflammatory processes in AD and their relation to other processes affecting the disease's progression.

Current Opinion in Neurobiology 2016, 36:74–81

This review comes from a themed issue on Neurobiology of disease

Edited by Dennis J Selkoe and Daniel R Weinberger

For a complete overview see the Issue and the Editorial

Available online 24th October 2015

http://dx.doi.org/10.1016/j.conb.2015.10.004

0959-4388/Published by Elsevier Ltd.

Section snippets

TREM2

One of the most significant recent findings to reinforce a role for immune dysfunction in AD is the association between enhanced LOAD risk and TREM2 gene mutations (see Table 1) [11]. TREM2, a microglial/macrophage cell surface receptor, activates an ITAM (Immunoreceptor tyrosine-based activation motif) signalling pathway via its trans-membrane binding partner TYROBP (also called DAP-12) (reviewed in [12]. Insight into the function of TREM2 stems from the identification of homozygous TREM2 and

CR1

The identification of complement receptor type 1 (CR1) [3, 7, 8] variants as risk-factors for LOAD further supports the link between immune dysfunction and AD. Since CR1, a multifunctional, single chain, type-1 transmembrane glycoprotein, is expressed on microglia, and blood cells such as erythrocytes. CR1 functions in the innate immune system to regulate the complement system and clearance of immune complexes, cell debris and also Aβ. Therefore, CR1 variants may contribute to LOAD by

CD33

CD33 is a type I transmembrane protein of the sialic acid-binding immunoglobulin-like lectins (SIGLECS) family and is expressed on haematopoietic and phagocytic cells including microglia [24••, 25•, 26•]. CD33 regulates innate immunity, possibly Aβ clearance and other neuroinflammatory processes (Figure 1).

The rs3865444 SNP proximal to CD33, found in LOAD GWAS studies [2, 4, 6] is associated with a lowered AD risk and is situated in the proximal promoter of CD33. It has been reported that the

MS4A cluster

This locus contains at least five genes implicated in immune modulation: MS4A3, MS4A2, MS4A6A, MS4A4A, MS4A4E and MS4A6E [1]. A number of SNPs have been identified near this cluster as AD risk alleles in LOAD GWAS [4, 6, 8]; rs983392 and rs610932 (minor T allele) (near MS4A6A) and rs4938933 (in intergenic region between MS4A4E and MS4A6A) associated with reduced AD risk, whilst rs670139 (in MS4A4E) and rs610932 (C allele near MS46A) associated with increased AD risk (Table 1). In humans, the

HLA-DRB5/HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1/Major Histocompatibility Complex, Class II, DR Beta 5)

The HLA-DRB5/HLA-DRB1 locus is a member of the Major Histocompatibility Complex Class II (MHCII), a highly polymorphic region involved in the immune response and histocompatibility [31]. HLA-DR, a component of MHCII, is highly expressed on reactive microglia in AD and PD brain, but mechanistic studies with regards to the role of HLA-DRB5/B1 in microglial dysfunction in AD are currently lacking.

APOE

Until recently, the E4 allele of APOE (Apolipoprotein E) was the only genetic risk factor associated with LOAD, and its important role in lipid metabolism connects this process to AD pathogenesis. Although APOE still remains the strongest risk factor for AD, different GWAS of LOAD cases have found many other variants in genes closely involved in lipid metabolism, such as CLU and ABCA7 [2, 3, 4, 6, 7, 8]. In the brain, astrocytes and microglia are the major APOE-expressing cells [26] and APOE

CLU

Clusterin (CLU), also known as Apolipoprotein J (ApoJ), is a chaperone protein that functions in apoptosis, complement regulation, lipid transport, membrane protection, and cell-cell interactions (Jones and Jomary, 2002). Similarly to APOE, the CLU gene encodes three alternative transcripts, and several SNPs have been identified that confer protection against LOAD [3, 7] (Table 1). Association of CLU with LOAD was also reported in the GWAS meta-analysis of 74,046 individuals. Furthermore CLU

ABCA7

ATP-binding cassette transporter A7 (ABCA7) is a member of the ATP-binding cassette family that are involved in lipid transport. Despite low ABCA7 expression in most human brain cells, microglia and neurons show the highest expression. ABCA7 is implicated in lipid metabolism, cholesterol efflux and inhibition of amyloid precursor protein (APP) processing in vitro [37] as well as the phagocytosis of apoptotic cells through C1q complement pathway in macrophages (Figure 1). Increased ABCA7

Conclusions

Recent GWAS-LOAD studies have found common variants in genes associated with three main processes; immune responses, lipid metabolism and endocytosis. Dysfunctional lipid metabolism and immune responses have been implicated in AD pathology for some time [5]. More recently, studies on the basis of genetic data indicate linkage between these two pathways. Moreover, genes like APOE, CLU and ABCA7 may represent a further crosstalk with the APP processing pathway, and gene mutations in TREM2 further

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We acknowledge funding by Complement UK/Alexion, Alzheimer's Research (ARUK), Ministerio de Educación del Perú  PRONABEC (Programa Nacional de Becas y Crédito Educativo) and an anonymous foundation.

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