An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain

Shaw, Benjamin; Snider, Henry C.; Turner, Alan; Zajac, Diana J.; Simpson, James; Estus, Steven

doi:10.3233/jad-215602

Cited by 15 publications

(24 citation statements)

References 39 publications

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“…As a new variant of TREM2 lacking exon 2 has recently been described in different areas of the human brain but not yet in the entorhinal cortex [ 45 , 46 , 47 ], we were interested to know if this isoform ( D2-TREM2 ) is also expressed in the entorhinal cortex. Thus, we confirmed its expression in the entorhinal cortex and observed that it was upregulated in AD samples (FC = 2.02, p -value < 0.05), being the second transcript of TREM2 most expressed; however, after adjusting for age and gender, the difference between AD samples and controls was no longer statistically significant (FC = 1.28, p -value = 0.50) ( Figure 3 B,C).…”

Section: Resultsmentioning

confidence: 99%

“…Sequences of primer pairs were designed using the Real-Time PCR tool (IDT, Coralville, IA, USA) and Primer3 software and D2-TREM2 primers described in Shaw B.C. et al [ 47 ] were included ( Supplementary Materials Table S1 ). The relative expression level of mRNA in a particular sample was calculated as previously described [ 80 ], and the geometric mean of GAPDH and ACTB genes was used as a reference to normalize expression values.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, it has been noted an increased expression of exons 3 and 4 depending on the degree of AD-related neurofibrillary pathology [ 44 ]. Moreover, a new variant of TREM2 lacking exon 2 has recently been described in the human brain [ 45 , 46 , 47 ]. It is interesting to note that epigenetic mechanisms involving TREM2 are also modulated in AD since TREM2 DNA methylation and hydroxymethylation levels are known to be altered in the hippocampus [ 48 ] and other brain regions affected by AD [ 49 , 50 , 51 ].…”

Section: Introductionmentioning

confidence: 99%

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Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Urdánoz‐Casado

Gordoa

Robles

et al. 2022

IJMS

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Genetic variants in TREM2, a microglia-related gene, are well-known risk factors for Alzheimer’s disease (AD). Here, we report that TREM2 originates from circular RNAs (circRNAs), a novel class of non-coding RNAs characterized by a covalent and stable closed-loop structure. First, divergent primers were designed to amplify circRNAs by RT-PCR, which were further assessed by Sanger sequencing. Then, additional primer sets were used to confirm back-splicing junctions. In addition, HMC3 cells were used to assess the microglial expression of circTREM2s. Three candidate circTREM2s were identified in control and AD human entorhinal samples. One of the circRNAs, circTREM2_1, was consistently amplified by all divergent primer sets in control and AD entorhinal cortex samples as well as in HMC3 cells. In AD cases, a moderate negative correlation (r = −0.434) was found between the global average area of Aβ deposits in the entorhinal cortex and circTREM2_1 expression level. In addition, by bioinformatics tools, a total of 16 miRNAs were predicted to join with circTREM2s. Finally, TREM2 mRNA corresponding to four isoforms was profiled by RT-qPCR. TREM2 mRNA levels were found elevated in entorhinal samples of AD patients with low or intermediate ABC scores compared to controls. To sum up, a novel circRNA derived from the TREM2 gene, circTREM2_1, has been identified in the human entorhinal cortex and TREM2 mRNA expression has been detected to increase in AD compared to controls. Unraveling the molecular genetics of the TREM2 gene may help to better know the innate immune response in AD.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Urdánoz‐Casado

Gordoa

Robles

et al. 2022

IJMS

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show abstract

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA and cDNA samples used for this study have been extensively described previously [ 22 , 23 , 24 , 25 ]. Briefly, RNA and genomic DNA were purified from anterior cingulate samples provided by the University of Kentucky AD Center, and the RNA was converted to cDNA as described [ 22 , 23 , 25 ]. Samples were divided into two groups based on AD neuropathology, as quantified by the National Institute on Aging–Reagan Institute (NIARI) criteria, which include both neuritic plaques and neurofibrillary tangles [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer’s Disease Genetics and Neuropathology

Turner

Shaw

Simpson

et al. 2022

Genes

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Elucidating the actions of genetic polymorphisms associated with the risk of Alzheimer’s disease (AD) may provide novel insights into underlying mechanisms. Two polymorphisms have implicated ABI3 as a modulator of AD risk. Here, we sought to identify ABI3 isoforms expressed in human AD and non-AD brain, quantify the more abundant isoforms as a function of AD genetics and neuropathology, and provide an initial in vitro characterization of the proteins produced by these novel isoforms. We report that ABI3 expression is increased with AD neuropathology but not associated with AD genetics. Single-cell RNAseq of APP/PS1 mice showed that Abi3 is primarily expressed by microglia, including disease-associated microglia. In human brain, several novel ABI3 isoforms were identified, including isoforms with partial or complete loss of exon 6. Expression of these isoforms correlated tightly with total ABI3 expression but were not influenced by AD genetics. Lastly, we performed an initial characterization of these isoforms in transfected cells and found that, while full-length ABI3 was expressed in a dispersed punctate fashion within the cytosol, isoforms lacking most or all of exon six tended to form extensive protein aggregates. In summary, ABI3 expression is restricted to microglia, is increased with Alzheimer’s neuropathology, and includes several isoforms that display a variable tendency to aggregate when expressed in vitro.

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Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Filipello¹,

You²,

Mirfakhar³

et al. 2023

Acta Neuropathol

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TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.

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An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain

Cited by 15 publications

References 39 publications

Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer’s Disease Genetics and Neuropathology

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

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