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Book: Presenilins and Alzheimer's disease

Younkin, Steven G.

with 4 tables

(Research and perspectives in Alzheimer's disease)

1998

Author's details	S. G. Younkin ... (ed.)
Series title	Research and perspectives in Alzheimer's disease
Keywords	Alzheimerkrankheit ; Preseniline
Subject	Alzheimer-Krankheit ; Alzheimersche Krankheit ; Alzheimer-Demenz ; Morbus Alzheimer ; Greisenblödsinn ; Alzheimer's Disease
Language	English
Size	XV, 100 S. : Ill., graph. Darst.
Publisher	Springer
Publishing place	Berlin u.a.
Document type	Book
HBZ-ID	HT009123722
ISBN	3-540-63997-7 ; 978-3-540-63997-8
Database	Catalogue ZB MED Medicine, Health

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1998 A 7004	order for loan	Magazin

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Article ; Online: Impact of variant-level batch effects on identification of genetic risk factors in large sequencing studies.

Wickland, Daniel P / Ren, Yingxue / Sinnwell, Jason P / Reddy, Joseph S / Pottier, Cyril / Sarangi, Vivekananda / Carrasquillo, Minerva M / Ross, Owen A / Younkin, Steven G / Ertekin-Taner, Nilüfer / Rademakers, Rosa / Hudson, Matthew E / Mainzer, Liudmila Sergeevna / Biernacka, Joanna M / Asmann, Yan W

PloS one

2021 Volume 16, Issue 4, Page(s) e0249305

Abstract: Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large ...

Abstract	Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large sample sizes for statistical power and therefore often inadvertently introduce batch effects because samples are typically collected, processed, and sequenced at multiple centers. Conventionally, batch effects are first detected and visualized using Principal Components Analysis and then controlled by including batch covariates in the disease association models. For sequencing-based genetic studies, because all variants included in the association analyses have passed sequencing-related quality control measures, this conventional approach treats every variant as equal and ignores the substantial differences still remaining in variant qualities and characteristics such as genotype quality scores, alternative allele fractions (fraction of reads supporting alternative allele at a variant position) and sequencing depths. In the Alzheimer's Disease Sequencing Project (ADSP) exome dataset of 9,904 cases and controls, we discovered hidden variant-level differences between sample batches of three sequencing centers and two exome capture kits. Although sequencing centers were included as a covariate in our association models, we observed differences at the variant level in genotype quality and alternative allele fraction between samples processed by different exome capture kits that significantly impacted both the confidence of variant detection and the identification of disease-associated variants. Furthermore, we found that a subset of top disease-risk variants came exclusively from samples processed by one exome capture kit that was more effective at capturing the alternative alleles compared to the other kit. Our findings highlight the importance of additional variant-level quality control for large sequencing-based genetic studies. More importantly, we demonstrate that automatically filtering out variants with batch differences may lead to false negatives if the batch discordances come largely from quality differences and if the batch-specific variants have better quality.
MeSH term(s)	Alleles ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Apolipoproteins E/genetics ; Databases, Genetic ; Exome ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Male ; Membrane Transport Proteins/genetics ; Mitochondrial Precursor Protein Import Complex Proteins ; Polymorphism, Single Nucleotide ; Principal Component Analysis ; Sequence Analysis, DNA
Chemical Substances	Apolipoproteins E ; Membrane Transport Proteins ; Mitochondrial Precursor Protein Import Complex Proteins ; TOMM40 protein, human
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0249305
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Article ; Online: Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

Younkin Steven G / Zou Fanggeng / Simmons Christopher R / Estus Steven

Molecular Neurodegeneration, Vol 6, Iss 1, p

2011 Volume 62

Abstract: Abstract Background Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate ... ...

Abstract	Abstract Background Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD. Results Seventeen non- APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines. Conclusions Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.
Keywords	Alzheimer ; genetics ; cholesterol ; GWAS ; SNP ; HMGCR ; statin ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2011-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease

Younkin Steven G / Zou Fanggeng / Simmons Christopher R / Estus Steven

Molecular Neurodegeneration, Vol 6, Iss 1, p

2011 Volume 33

Abstract: Abstract Background Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk ... ...

Abstract	Abstract Background Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. Results In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2 , which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). Conclusions RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.
Keywords	Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2011-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alzheimer's disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions.

The Journal of clinical investigation

2022 Volume 132, Issue 2

Abstract: Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer's disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from ... ...

Abstract	Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer's disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.
MeSH term(s)	Aged ; Alzheimer Disease/metabolism ; Brain/metabolism ; Female ; Humans ; Male ; Supranuclear Palsy, Progressive/metabolism ; Transcriptome
Language	English
Publishing date	2022-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI149904
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Article ; Online: The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer's disease: A cross-sectional study.

Matchett, Billie J / Lincoln, Sarah J / Baker, Matt / Tamvaka, Nikoleta / Labuzan, Sydney A / Hicks Sirmans, Tiffany N / Moloney, Christina M / Helminger, Jacqueline / Hinkle, Kelly M / Cabrera-Rodriguez, Janisse / Wickland, Daniel P / Johnson, Patrick W / Heckman, Michael G / Reddy, Joseph S / Younkin, Steven G / Carrasquillo, Minerva M / Duara, Ranjan / Graff-Radford, Neill R / Pottier, Cyril /

Ertekin-Taner, Nilüfer / Ross, Owen A / Rademakers, Rosa / Dickson, Dennis W / Murray, Melissa E

Medicine

2023 Volume 102, Issue 24, Page(s) e34017

Abstract: We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer's disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within ... ...

Abstract	We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer's disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60-73] vs 71 [63-77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10-15]) vs 9 [6-12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Cross-Sectional Studies ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Brain/pathology ; Hippocampus/metabolism ; tau Proteins/genetics ; tau Proteins/metabolism ; Protein C Inhibitor/metabolism
Chemical Substances	tau Proteins ; SERPINA5 protein, human ; Protein C Inhibitor
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000034017
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Article ; Online: Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures.

Sakae, Nobutaka / Heckman, Michael G / Vargas, Emily R / Carrasquillo, Minerva M / Murray, Melissa E / Kasanuki, Koji / Ertekin-Taner, Nilufer / Younkin, Steven G / Dickson, Dennis W

Journal of Alzheimer's disease : JAD

2019 Volume 70, Issue 3, Page(s) 659–666

Abstract: A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid ... ...

Abstract	A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOEɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.
MeSH term(s)	Aged ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid/metabolism ; Autopsy/methods ; Cerebral Amyloid Angiopathy/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Immunohistochemistry ; Male ; Microglia/metabolism ; Microglia/pathology ; Neuropathology/methods ; Outcome Assessment, Health Care
Chemical Substances	Amyloid
Language	English
Publishing date	2019-06-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-190451
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Article ; Online: Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk.

Simmons, Christopher R / Zou, Fanggeng / Younkin, Steven G / Estus, Steven

Molecular neurodegeneration

2011 Volume 6, Page(s) 62

Abstract: Background: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral ... ...

Abstract	Background: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD. Results: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines. Conclusions: Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.
Language	English
Publishing date	2011-08-25
Publishing country	England
Document type	Journal Article
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/1750-1326-6-62
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Article ; Online: Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease.

Simmons, Christopher R / Zou, Fanggeng / Younkin, Steven G / Estus, Steven

Molecular neurodegeneration

2011 Volume 6, Page(s) 33

Abstract: Background: Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors ... ...

Abstract	Background: Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. Results: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). Conclusions: RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.
Language	English
Publishing date	2011-05-19
Publishing country	England
Document type	Journal Article
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/1750-1326-6-33
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Article ; Online: Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains.

Ma, Li / Allen, Mariet / Sakae, Nobutaka / Ertekin-Taner, Nilufer / Graff-Radford, Neill R / Dickson, Dennis W / Younkin, Steven G / Sevlever, Daniel

Molecular neurodegeneration

2016 Volume 11, Issue 1, Page(s) 72

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Aged ; Aged, 80 and over ; Alternative Splicing ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Blotting, Western ; Brain/metabolism ; Female ; Gene Expression Profiling ; Genetic Variation ; Humans ; Male ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism ; Transcriptome
Chemical Substances	Membrane Glycoproteins ; Receptors, Immunologic ; TREM2 protein, human
Language	English
Publishing date	2016-11-25
Publishing country	England
Document type	Journal Article
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-016-0137-9
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