Neumann H, Daly MJ.
Variant TREM2 as risk factor for Alzheimer's disease.
N Engl J Med. 2013 Jan 10;368(2):182-4.
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Triggering receptor expressed on myeloid cells 2 (TREM2) represents a surface receptor without its own intracellular signaling motif. It therefore depends on the adaptor protein 12 (DAP12) for the initiation of signaling cascades. TREM2 has been primarily found and investigated in myeloid cells, and thus far, TREM2 and DAP12 mutations have only been known to be involved in progressive presenile dementia in patients suffering from polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease), a rare autosomal recessive disorder.
The reports from Jonsson et al. and Guerreiro et al. now convincingly suggest that rare, heterozygous variants of the TREM2 gene, which most likely result in a reduced function of this receptor, are pathogenetically involved in sporadic AD. In the human cerebral cortex, TREM2 expression has been described in microglia and, to a smaller extent, in neurons (Sessa et al., 2004). Importantly, TREM2 has been described to be expressed by non-activated microglia (Schmid et al., 2002), but also can be found at the border of amyloid-β (Aβ) plaque deposits in APP transgenic mice (Frank et al., 2008), thus implicating TREM2 in the innate immune response to Aβ accumulation and deposition in the brain.
Innate immune activation and neurodegenerative pathways interact at multiple levels, and this mutual interaction may ultimately function as an important motor of neurodegeneration (for a review see, e.g., (Lucin and Wyss-Coray, 2009; Heneka and O’Banion, 2007). Given the pro-phagocytic and anti-inflammatory role of TREM2 (Takahashi et al., 2005), expression of TREM2 by Aβ plaque-associated microglia may be interpreted as an effort to support Aβ clearance and to limit the proinflammatory cytokine expression in response to microglia activation by Aβ itself.
Knockdown of TREM2 in microglia increased the gene transcription of nitric oxide (NO) synthase 2 (NOS2) and tumor necrosis factor α (TNF-α) (Takahashi et al., 2005). As NOS2-derived NO may directly enhance Aβ aggregation (Kummer et al., 2011), and acts in concert with TNF-α to suppress hippocampal long-term potentiation (Wang et al., 2004; Wang et al., 2005), loss-of-function mutations in TREM2 may promote AD neuroinflammation and thereby drive neuronal degeneration. Likewise, TREM2 expression has been positively correlated with the phagocytic clearance of Aβ in APP transgenic mice (Melchior et al., 2010). Since impaired Aβ clearance has been suggested as the underlying cause of sporadic AD (Mawuenyega et al., 2010), loss of phagocytic efficacy due to TREM2 mutations could represent a possible mechanism by which the described mutations increase the risk to develop AD.
Further support for TREM2 being an important mediator in neuroinflammation comes from multiple sclerosis (MS), where soluble TREM2 has been found to be increased in patients suffering from relapsing-remitting and primary progressive MS (Piccio et al., 2008). Intriguingly, inhibition of TREM2 function potentiated pathology in the related murine model of experimental autoimmune encephalomyelitis (Piccio et al., 2007).
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The present work can be viewed as key support for the neuroinflammation hypothesis of Alzheimer’s disease. In my mind, at least, it dovetails well with earlier work demonstrating genomewide association between another microglial proinflammatory gene, complement receptor 1, and Alzheimer’s disease (Lambert et al., 2009). Together, these and other studies mark a turning of the tide in how we fundamentally view the disease—specifically, as an inflammatory syndrome.
In regard to the present work, I find it interesting that TREM2 expression was increased in the TgCRND8 mouse model of cerebral amyloidosis. One logical follow-on question is whether interrupting TREM2 function will impact disease progression in rodent models. Given that TREM2 plays a role in mediating proinflammatory innate immune signaling by microglia, as Michael Heneka nicely pointed out, one could hypothesize that blunting neuroinflammation by knocking out TREM2 would mitigate AD-like pathology in transgenic mice. By corollary, this would suggest that blocking TREM2-mediated neuroinflammation, as opposed to promoting it, would be the therapeutic approach here.
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Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
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These studies provide further evidence that the genetic architecture of Alzheimer's disease does indeed include rare variants of intermediate penetrance, analogous to our work on rare variants in the GRN (Brouwers et al., 2008) and CLU genes (Bettens et al., 2012). Moreover, these NEJM papers demonstrate the strength of techniques such as whole-exome sequencing to detect rare variants implicated in Alzheimer's disease, although it should be noted that large numbers of samples are required before there is sufficient basis to draw first conclusions. Of note, there was no evidence of association of the TREM2 variant in several individual replication cohorts, with the variant only reaching significance when pooling results.
One of the caveats when combining exome or genome sequence data from several sites, with controls and patients coming from different centers/platforms, is population stratification. Population allele frequency estimates seem to differ among countries. Nevertheless, association was also observed in one single large cohort from Iceland.
Discovery of a rare variant associated with AD, like the one described in TREM2, has a small epidemiological impact, but may have significant impact in understanding the pathomechanisms leading to AD.
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With the increasing acceptance (1) that Alzheimer’s disease is a multifactorial disorder (2), it might be a mistake to interpret every new finding on Alzheimer’s disease through the amyloid lens (see Michael Heneka’s comment above). As Neumann and Daly pointed out in their NEJM commentary, amyloid plaques have not been reported in Nasu-Hakola patients despite a near-complete loss of function of TREM2 and progressive presenile inflammatory neurodegeneration. Thus, increased AD risk in TREM2 variants is just as likely to be independent of amyloid, and future investigations should be designed/interpreted accordingly.
Looking back, we could argue that a similar mistake was made when epidemiological data on NSAIDs’ protective effects against developing AD were interpreted in terms of NSAIDs' ability to inhibit γ-secretase cleavage (3). This resulted in subsequent confusing data on various NSAIDs and Aβ production, and perhaps muddied NSAIDs' potential as therapeutic drugs. Perhaps we need to ponder whether our inability to think outside the amyloid framework is inhibiting the field from making faster progress towards an effective therapeutic treatment.
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