Inflammation is a well-established histologic feature in the brains of patients with Alzheimer’s disease. Complement factors were identified in amyloid plaques in the 1980s,21,22
followed by reports of clusters of activated microglia, complement-activation products, and cytokines in and near amyloid plaques.23–26
There is evidence that inflammation is an early event in the brains of patients with Alzheimer’s disease.27
It has also been noted that the expression of genes associated with inflammation in the brain is increased in aging and that this effect is accentuated in patients with Alzheimer’s disease.28
According to the amyloid hypothesis, which is the predominant theory about the pathogenesis of this disease, inflammation is a downstream effect of amyloidogenesis, which provides a trigger for the inflammatory response.
Genomewide association studies have also provided evidence of the importance of inflammation in Alzheimer’s disease. Thus, low-risk variants have been found in CR1
which belongs to the complement factor family of genes; in MS4A6A
which are members of a cell-surface gene family expressed in lymphoid tissue; and in CD33
which encodes a myeloid cell-surface receptor.
TREM2 was originally identified as a DAP12-associated receptor that was expressed on macrophages and dendritic cells32
and was later shown to be expressed on osteoclasts and microglia.33
TREM2 is a transmembrane glycoprotein, consisting of an extracellular immunoglobulin-like domain, a transmembrane domain, and a cytoplasmic tail, which associates with DAP12 for its signaling function.32,34
TREM2 has both exogenous ligands on pathogens and endogenous ligands that remain largely unknown, although a recent study has shown that Hsp60 is an agonist of TREM2 in neuroblastoma cells and astrocytes.35
In addition, an endogenous ligand on dendritic cells has been found.36
In brain cells, TREM2 is primarily expressed on microglia, the resident histiocytes of the central nervous system.37
Activation of microglia may lead to phagocytosis of cell debris and amyloid, but microglia can also be activated to promote the production of proinflammatory cytokines, or they may differentiate into antigen-presenting cells.38
A recent study showed that TREM2 expression is induced concomitantly with the formation of amyloid plaques in APP transgenic mice expressing the Swedish mutation (K670N/M671L) in APP
and this expression was found to correlate positively with amyloid phagocytosis by unactivated microglia.
The expression of TREM2 also correlated positively with the ability of microglia to stimulate the proliferation of CD4+ T cells, as well as the secretion of tumor necrosis factor and CCL2, but not interferon-γ
, into the extracellular milieu. This led the authors to speculate that TREM2-positive microglia on plaques capture and present self-antigens to lymphocytes infiltrating the central nervous system without promoting proinflammatory responses.39
Furthermore, knock-down of TREM2 or DAP12 in microglia resulted in reduced phagocytosis of apoptotic neurons, whereas the overexpression of TREM2 increased such phagocytosis,40
suggesting that microglia recognize and phagocytose apoptotic neurons through TREM2 ligation. TREM2 has an antiinflammatory function; it inhibits macrophage response to ligation of toll-like receptor (TLR),41
and it negatively regulates TLR-mediated maturation of dendritic cells, type I interferon responses, and the induction of antigen-specific T-cell proliferation.36
Furthermore, TREM2 stimulation of dendritic cells induces partial activation without any production of proinflammatory cytokines.34
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, which produces increased signals from the deep white matter of the brain on T2
-weighted magnetic resonance imaging, is called Nasu–Hakola disease. It is a rare recessively inherited disease that is characterized by painful bone cysts in wrists and ankles, psychotic symptoms, and progressive presenile dementia with onset in the fourth decade of life, usually leading to death in the fifth decade of life.42–44
Loss-of-function mutations in DAP12
were originally found in patients with Nasu–Hakola disease about a decade ago,45,46
suggesting that the TREM2–DAP12–mediated pathway may be important for human brain and bone tissue. Nasu–Hakola disease and Alzheimer’s disease are distinct from each other, and the clinical symptoms of Nasu–Hakola disease (early onset, painful bone cysts, fractures of bones of the limbs, and sclerosing leukoencephalopathy) are incompatible with the diagnosis of Alzheimer’s disease. Bearing in mind that it is possible that rare mutations accounting for a small proportion of cases of common diseases may define a clinical subgroup, we looked for but did not find clinical features (e.g., sex distribution, radiographic features, and rate of disease progression) that clearly separate carriers of the R47H mutation from noncarriers with Alzheimer’s disease, although the age at disease onset was on average 3.18 years earlier in the carriers than in the noncarriers.
A homozygous mutation in the 5′ consensus donor splice site in intron 1 of TREM2
in a Lebanese family, leading to early-onset dementia without bone cysts, has been reported.47
Furthermore, three homozygous mutations in TREM2
have recently been reported in three Turkish probands with frontotemporal dementia-like disease in the absence of bone cysts,48
and there is also a report of memory deficits in heterozygous carriers of a loss-of-function mutation in TREM2
in an Italian family.49
These findings suggest that TREM2 may be crucial for the integrity of cognitive function.
The R47H substitution encoded by rs75932628-T is located within the extracellular immunoglobulin-like domain of TREM2. The amino acid substitution may result in decreased affinity of TREM2 for its natural ligands and affect its signaling. It has recently been proposed that TREM2 may represent a proteolytic substrate for γ
-secretase, although the exact cleavage site was not identified.50
If this proteolytic activity is confirmed, processing of TREM2 may be affected by the R47H substitution.
In conclusion, we have found a new risk variant, rs75932628-T, for Alzheimer’s disease. Although this variant occurs with less frequency than the ApoE ε4 allele, it confers a risk of Alzheimer’s disease with an effect size that is similar to that of ApoE ε4. Given the involvement of TREM2 in the phagocytic role of microglia on amyloid plaques, it is possible that reduced TREM2 activity caused by the R47H substitution may lead to brain damage through the inability of the brain to clear these toxic products.