The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

Carmona, Susana; Zahs, Kathleen R.; Wu, Elizabeth; Dakin, Kelly; Brás, José; Guerreiro, Rita

doi:10.1016/s1474-4422(18)30232-1

Cited by 193 publications

(166 citation statements)

References 101 publications

(173 reference statements)

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“…Based on accumulating evidence from recent studies, a reduction in the activity of the TREM2 signalling pathway promotes neurodegeneration. 30,48 Because brain Aβ42 levels were comparable in App NL-F/wt knock-in mice and App NL-F/wt knock-in; ob/ob mice, soluble Aβ42 might not be targeted by microglia. Rather, the dysregulation of microglia may cause susceptibility to Aβ.…”

Section: Discussionmentioning

confidence: 99%

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

et al. 2019

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Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; APP, amyloid precursor protein; CNS, central nervous system; DEA, diethylamine; GFAP, glial fibrillary acidic protein; INSR, insulin receptor; IRS1, insulin receptor substrate-1; IRS2, insulin receptor substrate-2; PDK1, pyruvate dehydrogenase kinase 1; PSD95, post-synaptic density protein 95; SYT1, synaptotagmin 1; NF-H, neurofilament heavy chain. AbstractClinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/ diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/ diabetes and AD significantly reduce life expectancy. We generated App NL-F/wt knock-in; ob/ob mice by crossing App NL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. App NL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, App NL-F/wt knockin mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in App NL-F/wt knock-in mice and App NL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in App NL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and App NL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young App NL-F/wt knock-in; ob/ob mice. |SHINOHARA et Al.

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Section: Discussionmentioning

confidence: 99%

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

et al. 2019

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“…It was then that a pair of reports published back-to-back detailed findings that a rare SNP in TREM2 (resulting in amino acid change R47H) altered AD risk with the highest odds ratio of any AD risk gene outside of APOE (Figure 1) (Guerreiro et al, 2013a;Jonsson et al, 2013). More recent analysis has found an additional SNP variant in TREM2 that also reached statistical significance (R62H; (Sims et al, 2017)), and several other variants are more prevalent in AD patients than controls but have yet to reach significance or be replicated, likely in part due to their scarcity in the population (Carmona et al, 2018). In addition, homozygous TREM2 variants were also found to be casual for a form of FTD (Carmona et al, 2018;Chouery et al, 2008;Guerreiro et al, 2013a), while other variants significantly elevated FTD risk (Carmona et al, 2018;Giraldo et al, 2013).…”

Section: Trem2 Signaling Networkmentioning

confidence: 97%

“…Like DLB, the genetics of FTD is still a new field, however several studies have still identified links between FTD genetics and altered immune function and signaling (Broce et al, 2018;Carmona et al, 2018;Pottier et al, 2019). As previously discussed, the study of FTD is complicated by the significant pathological and clinical heterogeneity of the disorder.…”

Section: Evidence From Human Genetics Highlights Immunementioning

confidence: 99%

“…More recent analysis has found an additional SNP variant in TREM2 that also reached statistical significance (R62H; (Sims et al, 2017)), and several other variants are more prevalent in AD patients than controls but have yet to reach significance or be replicated, likely in part due to their scarcity in the population (Carmona et al, 2018). In addition, homozygous TREM2 variants were also found to be casual for a form of FTD (Carmona et al, 2018;Chouery et al, 2008;Guerreiro et al, 2013a), while other variants significantly elevated FTD risk (Carmona et al, 2018;Giraldo et al, 2013). While an initial report suggested an association between TREM2 R47H and Parkinson's disease (Rayaprolu et al, 2013), a more recent meta-analysis including those original results failed to replicate the findings (Lill et al, 2015).…”

Section: Trem2 Signaling Networkmentioning

confidence: 99%

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Immune Signaling in Neurodegeneration

2019

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Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-b, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.

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“…Genome wide association studies (GWAS) identify a number of coding variants highly expressed in microglia 12 . Of the GWAS identified risk factors, cluster of differentiation (CD) 33 and triggering receptor expressed on myeloid cells 2 (TREM2) have been shown to be involved in phagocytosis and response to stimuli when further examined both in vitro and in vivo 4,13,14 . Microglia harvested from aged dual amyloid precursor protein/presenilin 1 (APP swe PS1 ΔE9 ) model of AD also show decreased expression of Aβ binding receptors and Aβ degrading enzymes 15 .Similar to microglia, the type-I interferon (IFN) cytokine family are also critical in neuroinflammation.…”

mentioning

confidence: 99%

Abrogation of type-I interferon signalling alters the microglial response to Aβ1–42

Moore

Mobilio

Walker

et al. 2020

Sci Rep

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Neuroinflammation and accompanying microglial dysfunction are now appreciated to be involved in Alzheimer's disease (AD) pathogenesis. Critical to the process of neuroinflammation are the type-I interferon (IFN) family of cytokines. Efforts to phenotypically characterize microglia within AD identify distinct populations associated with type-I IFN signalling, yet how this affects underlying microglial function is yet to be fully elucidated. Here we demonstrate that Aβ 1-42 exposure increases bioactive levels of type-I IFN produced by primary microglia alongside increased expression of type-I IFN related genes. primary microglia isolated from brains of App swe PS1 ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aβ 1-42 . Correlative assessment of plaque sizes in aged App swe PS1 ΔE9 mice with abrogated type-I IFN signalling show unchanged deposition levels. Microglia from these mice did however show alterations in morphology. This data further highlights the role of type-I IFN signalling within microglia and identifies a role in phagocytosis. As such, targeting both microglial and global type-I IFN signalling presents as a novel therapeutic strategy for AD management.Alzheimer's disease (AD) is now recognised as the most common form of dementia and is now estimated to be the 5 th largest cause of death globally 1 . AD has been classically characterised by its two hallmark pathologies, neurofibrillary tangles composed of hyper phosphorylated tau, and extracellular senile plaques composed of amyloid beta (Aβ). The immune response to these pathologies, neuroinflammation is now appreciated to be involved in disease progression. Regulated forms of neuroinflammation are viewed as protective, and indeed required for homeostatic function. In contrast, a dysregulated form of this process is present in AD 2 . This dysregulated form is now recognised as a contributor to AD pathogenesis.Fundamental to this neuroinflammation are microglia, the resident innate immune cells within the central nervous system (CNS). Critically, microglia mount the initial neuroinflammatory response and further maintain it 3 . Upon recognition of noxious stimuli, microglia release a number of cytokines including interleukin (IL) 1β, IL6, and tumor necrosis factor alpha (TNFα) to create an inflammatory microenvironment 4 . This is seen in conjunction with chemokine secretion to recruit additional microglia. Microglia also have a number of roles outside immune-related functions. In particular, microglia are often viewed as macrophages of the CNS due to a shared hierarchal lineage and roles in phagocytosis 5 .Due to diverse roles, microglia adopt a number of varied phenotypes with differential corresponding functions throughout the CNS. As such, large efforts have been made to better phenotypically characterize microglia under both normal and AD settings, primarily through transcriptomic-based approaches 6,7 . In the 5× familial AD mouse model, a single cell ribonucleic acid (RNA) -seq approach was used t...

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The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

Cited by 193 publications

References 101 publications

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

Immune Signaling in Neurodegeneration

Abrogation of type-I interferon signalling alters the microglial response to Aβ1–42

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