Missense variant in TREML2 protects against Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Benitez BA
PROVIDER: S-EPMC3961557 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Previous studies in dementia epidemiology have reported higher Alzheimer's disease rates in African-Americans when compared with White Americans. To determine whether genetically determined African ancestry is associated with neuropathological changes commonly associated with dementia, we analyzed a population-based brain bank in the highly admixed city of São Paulo, Brazil. African ancestry was estimated through the use of previously described ancestry-informative markers. Risk of presence of neuritic plaques, neurofibrillary tangles, small vessel disease, brain infarcts and Lewy bodies in subjects with significant African ancestry versus those without was determined. Results were adjusted for multiple environmental risk factors, demographic variables and apolipoprotein E genotype. African ancestry was inversely correlated with neuritic plaques (P=0.03). Subjects with significant African ancestry (n=112, 55.4%) showed lower prevalence of neuritic plaques in the univariate analysis (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.55-0.95, P=0.01) and when adjusted for age, sex, APOE genotype and environmental risk factors (OR 0.43, 95% CI 0.21-0.89, P=0.02). There were no significant differences for the presence of other neuropathological alterations. We show for the first time, using genetically determined ancestry, that African ancestry may be highly protective of Alzheimer's disease neuropathology, functioning through either genetic variants or unknown environmental factors. Epidemiological studies correlating African-American race/ethnicity with increased Alzheimer's disease rates should not be interpreted as surrogates of genetic ancestry or considered to represent African-derived populations from the developing nations such as Brazil.
| S-EPMC3526728 | biostudies-literature
Project description:Alzheimer's disease (AD) represents the most common form of dementia in elder populations with approximately 30 million cases worldwide. Genome wide genotyping and sequencing studies have identified many genetic variants associated with late-onset Alzheimer's disease (LOAD). While most of these variants are associated with increased risk of developing LOAD, only limited number of reports focused on variants that are protective against the disease.Here we applied a novel approach to uncover protective alleles against AD by analyzing genetic and phenotypic data in Mount Sinai Biobank and Electronic Medical Record (EMR) databases.We discovered a likely loss-of-function small deletion variant in the caspase 7 (CASP7) gene associated with significantly reduced incidence of LOAD in carriers of the high-risk APOE ?4 allele. Further investigation of four independent cohorts of European ancestry revealed the protective effect of the CASP7 variant against AD is most significant in homozygous APOE ?4 allele carriers. Meta analysis of multiple datasets shows overall odds ratio?=?0.45 (p?=?0.004). Analysis of RNA sequencing derived gene expression data indicated the variant correlates with reduced caspase 7 expression in multiple brain tissues we examined.Taken together, these results are consistent with the notion that caspase 7 plays a key role in microglial activation driving neuro-degeneration during AD pathogenesis, and may explain the underlying genetic mechanisms that anti-inflammatory interventions in AD show greater benefit in APOE ?4 carriers than non-carriers. Our findings inform potential novel therapeutic opportunities for AD and warrant further investigations.
| S-EPMC4928152 | biostudies-literature
Project description:IntroductionThe genetic architecture of Alzheimer's disease (AD) is only partially understood.MethodsWe conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.ResultsWe identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10-10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10-10).DiscussionOur study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
| S-EPMC6408965 | biostudies-literature
Project description:Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease, which likely plays a critical role in the pathogenesis of disease. Increasing evidence suggests abnormal mitochondrial dynamics as important underlying mechanisms. In this study, we characterized marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of Alzheimer's disease mouse model CRND8 as early as 3?months of age before the accumulation of amyloid pathology. To establish the pathogenic significance of these abnormalities, we inhibited mitochondrial fragmentation by the treatment of mitochondrial division inhibitor 1 (mdivi-1), a mitochondrial fission inhibitor. Mdivi-1 treatment could rescue both mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the CRND8 neurons both in vitro and in vivo. More importantly, the amelioration of mitochondrial dynamic deficits by mdivi-1 treatment markedly decreased extracellular amyloid deposition and A?1-42/A?1-40 ratio, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters. Our findings support the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and Alzheimer's disease-related pathological and cognitive impairments in vivo and indicate the potential value of restoration of mitochondrial dynamics as an innovative therapeutic strategy for Alzheimer's disease.
| S-EPMC5886251 | biostudies-literature
Project description:The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.
| S-EPMC10799806 | biostudies-literature
Project description:The impairment of amyloid-? (A?) clearance in the brain plays a causative role in Alzheimer's disease (AD). Polarity distribution of aquaporin-4 (AQP4) is important to remove A? from brain. AQP4 polarity can be influenced by the ratio of two AQP4 isoforms M1 and M23 (AQP4-M1/M23), however, it is unknown whether the ratio of AQP4-M1/M23 changes in AD. Histone deacetylase 3 has been reported to be significantly increased in AD brain. Moreover, evidence indicated that microRNA-130a (miR-130a) possibly mediates the regulation of histone deacetylase 3 on AQP4-M1/M23 ratio by repressing the transcriptional activity of AQP4-M1 in AD. This study aimed to investigate whether intermittent fasting (IF), increasing the level of an endogenous histone deacetylases inhibitor ?-hydroxybutyrate, restores AQP4 polarity via miR-130a mediated reduction of AQP4-M1/M23 ratio in protection against AD. The results showed that IF ameliorated cognitive dysfunction, prevented brain from A? deposition, and restored the AQP4 polarity in a mouse model of AD (APP/PS1 double-transgenic mice). Additionally, IF down-regulated the expression of AQP4-M1 and histone deacetylase 3, reduced AQP4-M1/M23 ratio, and increased miR-130a expression in the cerebral cortex of APP/PS1 mice. In vitro, ?-hydroxybutyrate was found to down-regulate the expression of AQP4-M1 and histone deacetylase 3, reduce AQP4-M1/M23 ratio, and increase AQP4-M23 and miR-130a expression in 2 ?M A?-treated U251 cells. Interestingly, on the contrary to the result observed in 2 ?M A?-treated cells, AQP4 expression was obviously decreased in cells exposed to 10 ?M A?. miR-130a mimic decreased the expression of AQP4-M1 and the ratio of AQP4-M1/M23, as well as silencing histone deacetylase 3 caused the up-regulation of AQP4 and miR-130a, and the reduction of AQP4-M1/M23 ratio in U251 cells. In conclusion, IF exhibits beneficial effects against AD. The mechanism may be associated with recovery of AQP4 polarity, resulting from the reduction of AQP4-M1/M23 ratio. Furthermore, ?-hydroxybutyrate may partly mediate the effect of IF on the reduction of AQP4-M1/M23 ratio in AD, in which miR-130a and histone deacetylase 3 may be implicated.
| S-EPMC5712566 | biostudies-literature
Project description:Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.
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Project description:Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
| S-EPMC7200007 | biostudies-literature
Project description:Alzheimer's disease (AD) is a major public health concern worldwide and the few drugs currently available only treat the symptoms. Hence, there is a strong need to find more effective anti-AD agents. Cynanchum otophyllum is a traditional Chinese medicine for treating epilepsy, and otophylloside B (Ot B), isolated from C. otophyllum, is the essential active component. Having previously identified anti-aging effects of Ot B, we evaluated Ot B for AD prevention in C. elegans models of AD and found that Ot B extended lifespan, increased heat stress-resistance, delayed body paralysis, and increased the chemotaxis response. Collectively, these results indicated that Ot B protects against Aβ toxicity. Further mechanistic studies revealed that Ot B decreased Aβ deposition by decreasing the expression of Aβ at the mRNA level. Genetic analyses showed that Ot B mediated its effects by increasing the activity of heat shock transcription factor (HSF) by upregulating the expression of hsf-1 and its target genes, hsp-12.6, hsp-16.2 and hsp-70. Ot B also increased the expression of sod-3 by partially activating DAF-16, while SKN-1 was not essential in Ot B-mediated protection against Aβ toxicity.
| S-EPMC5397390 | biostudies-literature
Project description:Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
| S-EPMC4196723 | biostudies-literature