Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer’s disease brains
Open accessAbstract
BACKGROUND: Genetic analyses showed that the triggering receptor expressed in myeloid cells 2 (TREM2) p.R47H variant increases the risk for Alzheimer's disease (AD). The question of whether the p.R47H mutation affects expression or function of the receptor remains unanswered. To address this question we quantified mRNA and analyzed protein profiles of WT and p.R47H TREM2 in human brains. METHODS: Quantitative real-time PCR (qPCR) was performed using 2 sets of primers one that detects all TREM2 mRNA isoforms and one specific for the alternative spliced isoform (TREM2alt) that encodes for the extracellular domain (soluble TREM2). Because in the brain TREM2 is expressed primarily in microglial cells, we also assessed the levels of IBA1 to control for microglial variability across samples. For TREM2 protein quantitation and N-glycosylation processing, RIPA brain extracts were analyzed by Western blot before and after EndoH and PNGaseF treatments. RESULTS: We identified statistically significant increased levels of TREM2 transcripts in the temporal cortex of AD subjects when compared with controls; TREM2alt was likewise higher in AD cases, but was not significant after adjustment for covariates. Quantitative analysis of TREM2 protein confirmed qPCR results that showed higher levels in AD than in control brains. Among AD subjects, we observed a trend towards higher mRNA and protein TREM2 levels in carriers of the p.R47H risk allele. Analysis of individual TREM2 species found no difference in the relative amounts of mature and immature species, and carboxyl terminal fragments between non carriers and p.R47H samples. Furthermore, TREM2 species from either non carriers or p.R47H brains were equally susceptible to EndoH and PNGaseF treatments. CONCLUSIONS: Our results suggest that TREM2 expression is increased in AD. Furthermore, we provide evidence indicating that p.R47H mutation does not affect the levels of TREM2 either directly by altering expression or indirectly by affecting processing of the protein. Our data support previous findings that suggest that p.R47H variant affects TREM2 function by altering binding properties of the receptor rather than expression.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TREM2 was found to be up-regulated in brains of patients with AD.
“For example, another microglial AD risk gene, TREM2, was found to be up-regulated in brains of patients with AD (19).”
From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [19]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 21 · Cited by 70
Research works printed but not linked: 10
- [1]Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 2002 297 5580 353 6 10.1126/science.1072994 12130773 · DOI · Paper page
- [2]Zhang B Gaiteri C Bodea L-G Wang Z McElwee J Podtelezhnikov Alexei A Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease Cell 2013 153 3 707 20 10.1016/j.cell.2013.03.030 23622250 PMC3677161 · DOI · Paper page
- [5]Guerreiro R Wojtas A Bras J Carrasquillo M Rogaeva E Majounie E TREM2 variants in Alzheimer’s disease N Engl J Med 2013 368 2 117 27 10.1056/NEJMoa1211851 23150934 PMC3631573 · DOI · Paper page
- [6]Jonsson T Stefansson H Steinberg S Jonsdottir I Jonsson PV Snaedal J Variant of TREM2 associated with the risk of Alzheimer’s disease N Engl J Med 2013 368 2 107 16 10.1056/NEJMoa1211103 23150908 PMC3677583 · DOI · Paper page
- [7]Klesney-Tait J Turnbull IR Colonna M The TREM receptor family and signal integration Nat Immunol 2006 7 12 1266 73 10.1038/ni1411 17110943 · DOI
- [9]Paloneva J Mandelin J Kiialainen A Bohling T Prudlo J Hakola P DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features J Exp Med 2003 198 4 669 75 10.1084/jem.20030027 12925681 PMC2194176 · DOI · Paper page
- [10]Thrash JC Torbett BE Carson MJ Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease Neurochem Res 2009 34 1 38 45 10.1007/s11064-008-9657-1 18404378 PMC2655126 · DOI
- [12]Piccio L Buonsanti C Cella M Tassi I Schmidt RE Fenoglio C Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation Brain 2008 131 11 3081 91 10.1093/brain/awn217 18790823 PMC2577803 · DOI
- [16]Piccio L Deming Y Del-Aguila JL Ghezzi L Holtzman DM Fagan AM Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status Acta Neuropathol 2016 3 6 925 33 10.1007/s00401-016-1533-5 PMC4867123 26754641 · DOI · Paper page
- [19]Park J-S Ji IJ An HJ Kang M-J Kang S-W Kim D-H Disease-associated mutations of TREM2 Alter the processing of N-linked oligosaccharides in the golgi apparatus Traffic 2015 16 5 510 8 10.1111/tra.12264 25615530 · DOI
- Authors
- Ma, L., Allen, M., Sakae, N., Ertekin-Taner, N., Graff-Radford, N. R., Dickson, D. W., Younkin, S. G., & Sevlever, D.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Sevlever, Daniel
- Venue
- Molecular Neurodegeneration
- Published
- 2016-11-25
- Volume
- 11
- Issue
- 1
- Pages
- 72-72
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5124229
- OpenAlex
- W2556899666
- Cited by
- 70
- References
- 21
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 10 · 2022: 8 · 2021: 13 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 6
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R21 NS088928, R01 NS080820)
- National Institute of Aging (U01 AG046139, P50 AG16574)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, soluble TREM2, N-glycosylation, microglia, temporal cortex, risk alleles
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Membrane Glycoproteins, Receptors, Immunologic, Genetic Variation, Blotting, Western, Alternative Splicing, Gene Expression Profiling, Transcriptome, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
