The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

Bailey, Charles C.; DeVaux, Lindsey B.; Farzan, Michael

doi:10.1074/jbc.m115.677286

Cited by 240 publications

(278 citation statements)

References 37 publications

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“…More importantly, this process is dependent on the lipidation status of APOE, suggesting that apoE exerts its effects via manipulation of cellular cholesterol levels (87,140). More recently, the newly discovered AD risk gene that encodes the triggering receptor expressed on myeloid cells 2 (TREM2) (141,142) protein was found to have apoE as one of its ligands (143,144). Accordingly, TREM2-deficient microglia or microglia with an AD risk variant (R47H) lose the ability to effectively bind lipoproteins (including apoE), which decreases their phagocytic capabilities (145).…”

Section: Apoe and Cellular Metabolism Of Amentioning

confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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In 1907, the German psychiatrist, Alois Alzheimer, published a case report, "On an unusual illness of the cerebral cortex," in which he described what we now know as Alzheimer's disease (AD) (1). More than a century after this landmark discovery, AD is now recognized as the most common cause of late-life dementia. AD pathology is characterized by the cerebral accumulation of amyloid plaques and neurofibrillary tangles, both of which consist predominantly of specific insoluble protein aggregates. The majority of AD cases are sporadic and have a relatively late onset, predominantly after the age of 65. This form of AD is known as late-onset AD (LOAD), in contrast to early-onset AD, which has a strong genetic component, is often autosomal dominant, and accounts for less than 1% of AD cases (2). While most genetic risk factors for LOAD identified in the past two decades have a relatively small impact on AD risk, extensive epidemiological, clinical, and pathological studies have established the APOE gene on chromosome 19 as the most important genetic risk factor for developing LOAD (3-5). This locus encodes a 299 amino acid glycoprotein (apoE) that is expressed in several cell types, with highest expression levels found in the liver and the brain, where it is expressed predominantly by astrocytes (6) and, to a lesser extent, microglia (7,8). The human APOE gene Abstract Alzheimer's disease (AD) is one of the fastestgrowing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified APOE as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid- (A). Here, we discuss the role of apoE on the biophysical properties and metabolism of the A peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including A) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond A, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.

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Section: Apoe and Cellular Metabolism Of Amentioning

confidence: 99%

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Huynh

Davis

Ulrich

et al. 2017

Journal of Lipid Research

180

145

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“…TREM2 upregulation in such cells appears to accelerate their maturation and trafficking to lymph nodes and sites of infection, as well as stimulating the differentiation of Th2 or Th17 cells, dependent on the nature and concentration of the antigen presented [130,131]. The fact that TREM-2 acts as an ApoE receptor may also be of importance as this allows for an exaggerated effect of the ApoE4 protein in the context of dysfunctional TREM-2 receptors [132]. Moreover, a recent meta-analysis reported that increased methylation of the TREM2 promoter region appears to be an invariant feature in the brains of AD patients independently of age and sex [64].…”

Section: Influence Of Trem-2 Elevation In Pmbcsmentioning

confidence: 99%

“…There is also some evidence to suggest that increasing levels of neuroinflammation provoke further upregulation of the TREM-2 receptor on activated microglia allowing for an upwards spiral of inflammation via a positive feedback loop [153]. In addition, TREM-2 acts as an ApoE receptor [132], as discussed above, and in this context, it is noteworthy that recent studies have established a relationship between TREM-2 and ApoE in the regulation of the microglial phenotype and the level of inflammatory mediators excreted by these glial cells following activation [154,155]. In particular, evidence suggests that ApoE-mediated TREM-2 signalling provokes a change in microglial phenotype from tolerogenic to neurodegenerative following phagocytosis of apoptosed neurones in vivo [154] and the presence of the ApoE4 isoform is associated with higher levels of neuroinflammation in such circumstances by differentially increasing levels of TREM-2 [155].…”

Section: Abnormalities In Trem-2 Levels and Function As A Source Of Mmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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“…Recent accumulating evidence reveals an association between a diverse array of TREM2 variants and risk for AD and other neurodegenerative diseases [10][11][12]. These variants include mutations affecting TREM2 structure/function such as the generation of a truncated protein (W44X or W78X variants) [21], inability to associate with its intracellular adaptor, DAP12/TYROBP (K186N variant) [21], reduction in ligand binding ability (R47H variant) [22][23][24], alteration of subcellular localization (reduction on cell surface and increase in endoplasmic reticulum in T66M or Y38C variants) [18,25] and accelerated proteolytic loss from the cell surface (H157Y variant) [19,20]. Therefore, TREM2-related microglial dysfunction can potentially lead to the impairment of brain homeostasis including amyloid-β clearance, possibly leading to neuronal injury and cognitive dysfunction.…”

Section: Emerging Implications Of Trem2 and Strem2 In Neurodegeneratimentioning

confidence: 99%

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

Tanaka¹,

Inoue²,

Masuda³

et al. 2017

J Alzheimers Dis Parkinsonism

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The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

Cited by 240 publications

References 37 publications

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

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