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https://www.readbyqxmd.com/read/27814610/molecular-mechanisms-of-the-genetic-risk-factors-in-pathogenesis-of-alzheimer-disease
#1
Kunihiko Kanatsu, Taisuke Tomita
Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1. In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/27477018/trem2-binds-to-apolipoproteins-including-apoe-and-clu-apoj-and-thereby-facilitates-uptake-of-amyloid-beta-by-microglia
#2
Felix L Yeh, Yuanyuan Wang, Irene Tom, Lino C Gonzalez, Morgan Sheng
Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity...
July 20, 2016: Neuron
https://www.readbyqxmd.com/read/27458607/trem2-p-r47h-substitution-is-not-associated-with-dementia-with-lewy-bodies
#3
Ronald L Walton, Alexandra I Soto-Ortolaza, Melissa E Murray, Oswaldo Lorenzo-Betancor, Kotaro Ogaki, Michael G Heckman, Sruti Rayaprolu, Rosa Rademakers, Nilüfer Ertekin-Taner, Ryan J Uitti, Jay A van Gerpen, Zbigniew K Wszolek, Glenn E Smith, Kejal Kantarci, Val J Lowe, Joseph E Parisi, David T Jones, Rodolfo Savica, Jonathan Graff-Radford, David S Knopman, Ronald C Petersen, Neill R Graff-Radford, Tanis J Ferman, Dennis W Dickson, Bradley F Boeve, Owen A Ross, Catherine Labbé
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, α-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD)...
August 2016: Neurology. Genetics
https://www.readbyqxmd.com/read/27302364/genetic-variations-underlying-alzheimer-s-disease-evidence-from-genome-wide-association-studies-and-beyond
#4
REVIEW
Elise Cuyvers, Kristel Sleegers
With the advent of genome-wide association studies (GWAS) and next-generation sequencing, more than 20 risk loci that affect Alzheimer's disease have been identified. These loci are estimated to explain about 28% of the heritability of liability, 30% of familial risk, and over 50% of sibling recurrence risk of developing Alzheimer's disease. These estimates are high in comparison with those for other complex diseases for which more risk loci have been discovered, such as type 2 diabetes, which is mostly a result of the strong effect of APOE ɛ4 and to a lesser extent the rare variant TREM2 p...
July 2016: Lancet Neurology
https://www.readbyqxmd.com/read/27100611/targeting-microglia-for-the-treatment-of-alzheimer-s-disease
#5
REVIEW
Paul D Wes, Faten A Sayed, Frédérique Bard, Li Gan
While histological changes in microglia have long been recognized as a pathological feature of Alzheimer's disease (AD), recent genetic association studies have also strongly implicated microglia in the etiology of the disease. Coding and noncoding polymorphisms in several genes expressed in microglia-including APOE, TREM2, CD33, GRN, and IL1RAP-alter AD risk, and therefore could be considered as entry points for therapeutic intervention. Furthermore, microglia may have a substantial effect on current amyloid β (Aβ) and tau immunotherapy approaches, since they are the primary cell type in the brain to mediate Fc receptor-facilitated antibody effector function...
October 2016: Glia
https://www.readbyqxmd.com/read/26973105/the-effect-of-increased-genetic-risk-for-alzheimer-s-disease-on-hippocampal-and-amygdala-volume
#6
Michelle K Lupton, Lachlan Strike, Narelle K Hansell, Wei Wen, Karen A Mather, Nicola J Armstrong, Anbupalam Thalamuthu, Katie L McMahon, Greig I de Zubicaray, Amelia A Assareh, Andrew Simmons, Petroula Proitsi, John F Powell, Grant W Montgomery, Derrek P Hibar, Eric Westman, Magda Tsolaki, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Velas, Simon Lovestone, Henry Brodaty, David Ames, Julian N Trollor, Nicholas G Martin, Paul M Thompson, Perminder S Sachdev, Margaret J Wright
Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer's disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults...
April 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/26971934/molecular-basis-of-familial-and-sporadic-alzheimer-s-disease
#7
REVIEW
Jolanta Dorszewska, Michal Prendecki, Anna Oczkowska, Mateusz Dezor, Wojciech Kozubski
Alzheimer's disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1)...
2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/26507310/evaluating-pathogenic-dementia-variants-in-posterior-cortical-atrophy
#8
Minerva M Carrasquillo, Imelda Barber, Sarah J Lincoln, Melissa E Murray, Gamze Balci Camsari, Qurat ul Ain Khan, Thuy Nguyen, Li Ma, Gina D Bisceglio, Julia E Crook, Steven G Younkin, Dennis W Dickson, Bradley F Boeve, Neill R Graff-Radford, Kevin Morgan, Nilüfer Ertekin-Taner
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array...
January 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/26449541/interaction-between-variants-in-clu-and-ms4a4e-modulates-alzheimer-s-disease-risk
#9
Mark T W Ebbert, Kevin L Boehme, Mark E Wadsworth, Lyndsay A Staley, Shubhabrata Mukherjee, Paul K Crane, Perry G Ridge, John S K Kauwe
INTRODUCTION: Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. METHODS: We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants...
February 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/26438529/genetics-ignite-focus-on-microglial-inflammation-in-alzheimer-s-disease
#10
REVIEW
Manasi Malik, Ishita Parikh, Jared B Vasquez, Conor Smith, Leon Tai, Guojun Bu, Mary Jo LaDu, David W Fardo, G William Rebeck, Steven Estus
In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis...
2015: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/26374899/apolipoprotein-e-is-a-ligand-for-triggering-receptor-expressed-on-myeloid-cells-2-trem2
#11
Yuka Atagi, Chia-Chen Liu, Meghan M Painter, Xiao-Fen Chen, Christophe Verbeeck, Honghua Zheng, Xia Li, Rosa Rademakers, Silvia S Kang, Huaxi Xu, Steven Younkin, Pritam Das, John D Fryer, Guojun Bu
Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons...
October 23, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26374897/the-triggering-receptor-expressed-on-myeloid-cells-2-binds-apolipoprotein-e
#12
Charles C Bailey, Lindsey B DeVaux, Michael Farzan
The triggering receptor expressed on myeloid cells 2 (TREM2) is an Ig-like V-type receptor expressed by populations of myeloid cells in the central nervous system and periphery. Loss-of-function mutations in TREM2 cause a progressive, fatal neurodegenerative disorder called Nasu-Hakola disease. In addition, a TREM2 R47H coding variant was recently identified as a risk factor for late-onset Alzheimer disease. TREM2 binds various polyanionic molecules but no specific protein ligands have been identified. Here we show that TREM2 specifically binds apolipoprotein E, a well established participant in Alzheimer disease...
October 23, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26232392/inflammation-in-alzheimer-s-disease-and-molecular-genetics-recent-update
#13
REVIEW
Zhi-Gang Zhang, Yan Li, Cheung Toa Ng, You-Qiang Song
Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease...
October 2015: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/26071899/rna-sequencing-reveals-transcriptional-up-regulation-of-trem2-in-response-to-bexarotene-treatment
#14
Iliya Lefterov, Jonathan Schug, Anais Mounier, Kyong Nyon Nam, Nicholas F Fitz, Radosveta Koldamova
We have recently demonstrated that short term bexarotene treatment of APP/PS1 mice significantly improves their cognitive performance. While there were no changes in plaque load, or insoluble Aβ levels in brain, biochemical analysis strongly suggested improved clearance of soluble Aβ, including Aβ oligomers. To get further insight into molecular mechanisms underlying this therapeutic effect, we explored genome-wide differential gene expression in brain of bexarotene and control treated APP/PS1 mice. We performed high throughput massively parallel sequencing on mRNA libraries generated from cortices of bexarotene or vehicle treated APP/PS1 mice and compared the expression profiles for differential gene expression...
October 2015: Neurobiology of Disease
https://www.readbyqxmd.com/read/25948718/homozygous-carriers-of-app-a713t-mutation-in-an-autosomal-dominant-alzheimer-disease-family
#15
Maria E Conidi, Livia Bernardi, Gianfranco Puccio, Nicoletta Smirne, Maria G Muraca, Sabrina A M Curcio, Rosanna Colao, Paola Piscopo, Maura Gallo, Maria Anfossi, Francesca Frangipane, Alessandra Clodomiro, Maria Mirabelli, Franca Vasso, Chiara Cupidi, Giusi Torchia, Raffaele Di Lorenzo, Paola Mandich, Annamaria Confaloni, Raffaele G Maletta, Amalia C Bruni
OBJECTIVE: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. METHODS: The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma β-amyloid peptide was measured...
June 2, 2015: Neurology
https://www.readbyqxmd.com/read/25664220/the-role-of-trem2-in-alzheimer-s-disease-and-other-neurological-disorders
#16
Faris Yaghmoor, Ahmed Noorsaeed, Samar Alsaggaf, Waleed Aljohani, Henrieta Scholtzova, Allal Boutajangout, Thomas Wisniewski
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele...
November 2014: Journal of Alzheimer's Disease and Parkinsonism
https://www.readbyqxmd.com/read/25593125/different-mechanisms-of-apolipoprotein-e-isoform-dependent-modulation-of-prostaglandin-e2-production-and-triggering-receptor-expressed-on-myeloid-cells-2-trem2-expression-after-innate-immune-activation-of-microglia
#17
Xianwu Li, Kathleen S Montine, C Dirk Keene, Thomas J Montine
Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice...
May 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/25311924/genetics-of-alzheimer-s-disease
#18
REVIEW
Vincent Chouraki, Sudha Seshadri
Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease-modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets...
2014: Advances in Genetics
https://www.readbyqxmd.com/read/25186855/the-rare-trem2-r47h-variant-exerts-only-a-modest-effect-on-alzheimer-disease-risk
#19
Basavaraj V Hooli, Antonio R Parrado, Kristina Mullin, Wai-Ki Yip, Tian Liu, Johannes T Roehr, Dandi Qiao, Frank Jessen, Oliver Peters, Tim Becker, Alfredo Ramirez, Christoph Lange, Lars Bertram, Rudolph E Tanzi
OBJECTIVES: Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the "triggering receptor expressed on myeloid cells 2" (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE ε4 allele. METHODS: In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls...
October 7, 2014: Neurology
https://www.readbyqxmd.com/read/25114068/genetic-determinants-of-disease-progression-in-alzheimer-s-disease
#20
Xingbin Wang, Oscar L Lopez, Robert A Sweet, James T Becker, Steven T DeKosky, Mahmud M Barmada, F Yesim Demirci, M Ilyas Kamboh
There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as "rapid progressors" if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and "slow progressors" if the MMSE changed ≤2 points...
2015: Journal of Alzheimer's Disease: JAD
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