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1.
Proc Natl Acad Sci U S A ; 120(36): e2302720120, 2023 09 05.
Article in English | MEDLINE | ID: mdl-37643212

ABSTRACT

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.


Subject(s)
Alzheimer Disease , HLA-DRB1 Chains , Parkinson Disease , Humans , Alzheimer Disease/genetics , Histocompatibility Antigens , HLA Antigens , HLA-DRB1 Chains/genetics , Parkinson Disease/genetics
2.
Int J Mol Sci ; 24(8)2023 Apr 18.
Article in English | MEDLINE | ID: mdl-37108578

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic alterations such as abnormal insulin and lipid metabolism and have some common genetic factors such as APOE genotype. Taking this into account, we hypothesized that we could identify common genetic factors involved in the development of diabetes and cardiovascular diseases. METHODOLOGY: We first genotyped 48 single nucleotide polymorphisms (SNPs) previously associated with AD in a cohort composed of 330 patients with cognitive impairment (CI) to assess their association with plasma lipids. Second, we conducted pleiotropy-informed conjunctional false discovery rate (FDR) analysis designed to identify shared variants between AD and plasma lipid levels. Finally, we used the SNPs to be found associated with lipid parameters and AD to search for associations with lipoprotein parameters in 281 patients with cardiometabolic risk. RESULTS: Five SNPs were significantly associated with lower levels of cholesterol transported in remnant lipoprotein particles (RLPc) in subjects with CI; among these SNPs was the rs73572039 variant in PVRL2. Stratified QQ-plots were conducted on GWAS designed for AD and triglycerides (TG). The cross-trait analysis resulted in a total of 22 independent genomic loci associated with both AD and TG levels with a conjFDR < 0.05. Among these loci, two pleiotropic variants were located in PVRL2 (rs12978931 and rs11667640). The three SNPs in PVRL2 were significantly associated with RLPc, TG, and number of circulating VLDL and HDL particles in subjects with cardiometabolic risk. CONCLUSIONS: We have identified three variants in PVRL2 that predispose individuals to AD that also influence the lipid profile that confers cardiovascular risk in T2DM subjects. PVRL2 is a potential new modulating factor of atherogenic dyslipidemia.


Subject(s)
Alzheimer Disease , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Dyslipidemias , Metabolic Syndrome , Humans , Alzheimer Disease/genetics , Alzheimer Disease/complications , Cardiovascular Diseases/genetics , Cholesterol , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Dyslipidemias/genetics , Dyslipidemias/complications , Genome-Wide Association Study , Metabolic Syndrome/genetics , Metabolic Syndrome/complications , Polymorphism, Single Nucleotide , Triglycerides
3.
Int J Mol Sci ; 24(2)2023 Jan 04.
Article in English | MEDLINE | ID: mdl-36674414

ABSTRACT

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Male , Female , Alzheimer Disease/genetics , Chromosomes, Human, Y/genetics , Genome-Wide Association Study , Mosaicism , Risk Factors , Cognitive Dysfunction/genetics , tau Proteins/genetics , Biomarkers , Amyloid beta-Peptides/genetics
4.
Med Microbiol Immunol ; 209(4): 489-498, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32500359

ABSTRACT

Different members of the tetraspanin superfamily have been described to regulate different virus infectious cycles at several stages: viral entry, viral replication or virion exit or infectivity. In addition, tetraspanin CD81 regulates HIV reverse transcription through its association with the dNTP hydrolase SAMHD1. Here we aimed at analysing the role of CD81 in Herpes simplex virus 1 infectivity using a neuroblastoma cell model. For this purpose, we generated a CD81 KO cell line using the CRISPR/Cas9 technology. Despite being CD81 a plasma membrane protein, CD81 KO cells showed no defects in viral entry nor in the expression of early protein markers. In contrast, glycoprotein B and C, which require viral DNA replication for their expression, were significantly reduced in CD81 KO infected cells. Indeed, HSV-1 DNA replication and the formation of new infectious particles were severely compromised in CD81 KO cells. We could not detect significant changes in SAMHD1 total expression levels, but a relocalization into endosomal structures was observed in CD81 KO cells. In summary, CD81 KO cells showed impaired viral DNA replication and produced greatly diminished viral titers.


Subject(s)
Herpesviridae Infections/virology , Herpesvirus 1, Human/physiology , Tetraspanin 28/genetics , Tetraspanin 28/metabolism , CRISPR-Cas Systems , Cell Line, Tumor , Gene Knockout Techniques , Herpesvirus 1, Human/pathogenicity , Humans , SAM Domain and HD Domain-Containing Protein 1/metabolism , Viral Envelope Proteins/metabolism , Virion/metabolism , Virus Internalization , Virus Replication
5.
Biomolecules ; 14(5)2024 May 20.
Article in English | MEDLINE | ID: mdl-38786010

ABSTRACT

Cholesterol, a crucial component of cell membranes, influences various biological processes, including membrane trafficking, signal transduction, and host-pathogen interactions. Disruptions in cholesterol homeostasis have been linked to congenital and acquired conditions, including neurodegenerative disorders such as Alzheimer's disease (AD). Previous research from our group has demonstrated that herpes simplex virus type I (HSV-1) induces an AD-like phenotype in several cell models of infection. This study explores the interplay between cholesterol and HSV-1-induced neurodegeneration. The impact of cholesterol was determined by modulating its levels with methyl-beta-cyclodextrin (MßCD) using the neuroblastoma cell lines SK-N-MC and N2a. We have found that HSV-1 infection triggers the intracellular accumulation of cholesterol in structures resembling endolysosomal/autophagic compartments, a process reversible upon MßCD treatment. Moreover, MßCD exhibits inhibitory effects at various stages of HSV-1 infection, underscoring the importance of cellular cholesterol levels, not only in the viral entry process but also in subsequent post-entry stages. MßCD also alleviated several features of AD-like neurodegeneration induced by viral infection, including lysosomal impairment and intracellular accumulation of amyloid-beta peptide (Aß) and phosphorylated tau. In conclusion, these findings highlight the connection between cholesterol, neurodegeneration, and HSV-1 infection, providing valuable insights into the underlying mechanisms of AD.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Cholesterol , Herpes Simplex , Herpesvirus 1, Human , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/physiology , Cholesterol/metabolism , Humans , Amyloid beta-Peptides/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/virology , Alzheimer Disease/pathology , Alzheimer Disease/drug therapy , Herpes Simplex/virology , Herpes Simplex/metabolism , Herpes Simplex/drug therapy , Herpes Simplex/pathology , Cell Line, Tumor , Animals , beta-Cyclodextrins/pharmacology , Lysosomes/metabolism , Lysosomes/drug effects , tau Proteins/metabolism , Phenotype , Mice
6.
Microorganisms ; 11(5)2023 May 04.
Article in English | MEDLINE | ID: mdl-37317179

ABSTRACT

An increasing body of evidence strongly suggests that infections or reactivations of herpes simplex virus type 1 (HSV-1) may be closely linked to Alzheimer's disease (AD). Promising results have been obtained using cell and animal models of HSV-1 infection, contributing to the understanding of the molecular mechanisms linking HSV-1 infection and AD neurodegeneration. ReNcell VM is a human neural stem cell line that has been used as a model system to study the impact of various infectious agents on the central nervous system. In this study, we demonstrate the suitability of the ReNcell VM cell line for developing a new in vitro model of HSV-1 infection. By following standard differentiation protocols, we were able to derive various nervous cell types, including neurons, astrocytes, and oligodendrocytes, from neural precursors. Additionally, we demonstrated the susceptibility of ReNcell VM cells, including precursor and differentiated cells, to HSV-1 infection and subsequent viral-induced AD-like neurodegeneration. Our findings support the use of this cell line to generate a new research platform for investigating AD neuropathology and its most significant risk factors, which may lead to important discoveries in the context of this highly impactful disease.

7.
JAMA Netw Open ; 6(5): e2313734, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37195665

ABSTRACT

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.


Subject(s)
Alzheimer Disease , Humans , Female , Aged , Aged, 80 and over , Male , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Cholesterol, HDL , Risk Factors , Causality
8.
Antiviral Res ; 192: 105116, 2021 08.
Article in English | MEDLINE | ID: mdl-34107282

ABSTRACT

Growing evidence supports that chronic or latent infection of the central nervous system might be implicated in Alzheimer's disease (AD). Among them, Herpes simplex virus type 1 (HSV-1) has emerged as a major factor in the etiology of the disease. Our group is devoted to the study of the relationship among HSV-1, oxidative stress (OS) and neurodegeneration. We have found that HSV-1 induces the main neuropathological hallmarks of AD, including the accumulation of intracellular amyloid beta (Aß), hyperphosphorylated tau protein and autophagic vesicles, that OS exacerbates these effects, and that matrix metalloproteinase 14 (MMP-14) participates in the alterations induced by OS. In this work, we focused on the role of MMP-14 in the degenerative markers raised by HSV-1 infection. Interestingly, we found that MMP-14 blockage is a potent inhibitor of HSV-1 infection efficiency, that also reduces the degeneration markers, accumulation of Aß and hyperphosphorylated tau, induced by the virus. Our results point to MMP-14 as a potent antiviral target to control HSV-1 infection and its associated neurodegenerative effects.


Subject(s)
Herpes Simplex/metabolism , Herpesvirus 1, Human/physiology , Matrix Metalloproteinase 14/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/virology , Amyloid beta-Peptides/metabolism , Animals , Antiviral Agents/pharmacology , Autophagosomes/metabolism , Biomarkers/metabolism , Cell Line, Tumor , Herpes Simplex/virology , Herpesvirus 1, Human/drug effects , Humans , Matrix Metalloproteinase 14/deficiency , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Neuroblastoma/pathology , Oxidative Stress , Phosphorylation , tau Proteins/metabolism
9.
Neurochem Int ; 146: 105032, 2021 06.
Article in English | MEDLINE | ID: mdl-33781848

ABSTRACT

Mounting evidence suggests a major role of infectious agents in the pathogenesis of sporadic Alzheimer's disease (AD). Among them, herpes simplex virus type 1 (HSV-1) infection has emerged as a major factor in the etiology of AD. HSV-1 is able to induce some of the main alterations of the disease such as hyperphosphorylation of tau protein and accumulation of amyloid-ß peptide. Functional genomic analysis of a cell model of HSV-1 infection and oxidative stress developed in our laboratory revealed lysosomal system to be the main pathway altered, and the lysosome-associated membrane protein 2 (LAMP2) gene one of the most strongly modulated genes. The aim of this work is to study LAMP2 as an AD candidate gene and to investigate its role in the neurodegeneration induced by HSV-1 using a LAMP2 knockdown cell model. LAMP2 deficiency led to a significant reduction of viral DNA replication and formation of infectious particles. In addition, tau hyperphosphorylation and inhibition of Aß secretion induced by the virus were attenuated by the absence of LAMP2. Finally, genetic association studies revealed LAMP2 genetic variants to be associated with AD risk. In summary, our data indicate that LAMP2 could be a suitable candidate to mediate the AD-like phenotype caused by HSV-1.


Subject(s)
Alzheimer Disease/metabolism , Herpes Simplex/metabolism , Herpes Simplex/prevention & control , Herpesvirus 1, Human/metabolism , Lysosomal-Associated Membrane Protein 2/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/virology , Animals , Cell Line, Tumor , Female , Gene Knockdown Techniques/methods , Herpes Simplex/genetics , Humans , Lysosomal-Associated Membrane Protein 2/antagonists & inhibitors , Lysosomal-Associated Membrane Protein 2/genetics , Male , Mice , Middle Aged , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/virology
10.
J Pers Med ; 11(12)2021 Dec 07.
Article in English | MEDLINE | ID: mdl-34945790

ABSTRACT

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

11.
BMC Med Genet ; 11: 32, 2010 Feb 25.
Article in English | MEDLINE | ID: mdl-20184726

ABSTRACT

BACKGROUND: Interleukin (IL)-1beta is a potent proinflammatory cytokine markedly overexpressed in the brains of patients with Alzheimer's disease (AD), and also involved in development of atherosclerosis and coronary artery disease. Caspase-1 (CASP1), formerly called IL-1beta converting enzyme (ICE), mediates the cleavage of the inactive precursor of IL-1beta into the biologically active form. CASP1 genetic variation (G+7/in6A, rs501192) has been associated with susceptibility to myocardial infarction and cardiovascular death risk. We examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CASP1 by genotyping haplotype tagging SNPs (htSNPs) (rs501192, rs556205 and rs530537) in a group of 628 Spanish AD cases and 722 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CASP1 genetic variations are causally related to AD risk.


Subject(s)
Alzheimer Disease/genetics , Caspase 1/genetics , Age Factors , Aged , Aged, 80 and over , Apolipoprotein E4/genetics , Female , Genetic Variation , Genotype , Haplotypes , Humans , Interleukin-1beta/metabolism , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Sex Factors
12.
Oxid Med Cell Longev ; 2020: 5917187, 2020.
Article in English | MEDLINE | ID: mdl-33282112

ABSTRACT

The alteration of amyloid precursor protein (APP) proteolysis is a hallmark of Alzheimer's disease (AD). Recent studies have described noncanonical pathways of APP processing that seem partly executed by lysosomal enzymes. Our laboratory's in vitro human SK-N-MC model has shown that oxidative stress (OS) alters the lysosomal degradation pathway and the processing/metabolism of APP. The present study identifies the lysosomal protein matrix metalloproteinase 14 (MMP14) as a protease involved in the APP noncanonical processing. Previous expression analyses of the above cells showed MMP14 to be overexpressed under OS. In the present work, its role in changes in OS-induced APP proteolysis and lysosomal load was examined. The results show that MMP14 mediates the accumulation of an ≈85 kDa N-terminal APP fragment and increases the lysosome load induced by OS. These results were validated in neurons and neural progenitor cells generated from the induced pluripotent stem cells of patients with sporadic AD, reinforcing the idea that MMP14 may offer a therapeutic target in this disease.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Lysosomes/metabolism , Matrix Metalloproteinase 14/metabolism , Neurons/metabolism , Oxidative Stress/physiology , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Humans , Proteolysis
13.
BMC Med Genet ; 10: 129, 2009 Dec 08.
Article in English | MEDLINE | ID: mdl-19995442

ABSTRACT

BACKGROUND: As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs) (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976) in a group of 634 Spanish AD cases and 733 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists.


Subject(s)
Alzheimer Disease/genetics , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Aged , Aged, 80 and over , Case-Control Studies , Cohort Studies , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Spain , Dyrk Kinases
14.
J Alzheimers Dis ; 68(4): 1535-1547, 2019.
Article in English | MEDLINE | ID: mdl-30909233

ABSTRACT

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.


Subject(s)
Adaptor Proteins, Vesicular Transport/genetics , Alzheimer Disease/genetics , Brain-Derived Neurotrophic Factor/genetics , Dopamine beta-Hydroxylase/genetics , Epistasis, Genetic , Aged , Aged, 80 and over , Female , Genetic Loci , Genetic Predisposition to Disease , Genotype , Humans , Male , Polymorphism, Single Nucleotide , Sex Factors
15.
Dement Geriatr Cogn Disord ; 26(5): 440-4, 2008.
Article in English | MEDLINE | ID: mdl-18957849

ABSTRACT

Mutations of presenilin 1 (PSEN1) are associated with monogenic Alzheimer's disease (AD); polymorphisms at this gene may therefore be associated with the sporadic form of the disease. In fact, recent meta-analyses and whole-genome association studies indicate PSEN1 as one of the few genes significantly associated with AD risk. Several polymorphisms have been analyzed in PSEN1. The present work examined the possible modulation of the risk of AD by a PSEN1 polymorphism (dbSNP rs3025786) located in intron 7, which we found during a denaturing gradient gel electrophoresis mutation screening of the gene, and which was previously reported as 'suspected' in the public databases. The study of a Spanish case-control sample of 1,183 individuals showed this polymorphism to be associated with AD in an apolipoprotein E (APOE)-specific manner: more specifically, to carry the PSEN1 C allele was associated with a decreased AD risk among carriers of the APOE4 allele. Thus, the present results reinforce the possible involvement of PSEN1 in sporadic AD.


Subject(s)
Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Presenilin-1/genetics , Aged , Alleles , Alzheimer Disease/epidemiology , Alzheimer Disease/psychology , DNA Probes , Female , Genotype , Heterozygote , Humans , Male , Polymorphism, Genetic/genetics , Psychiatric Status Rating Scales , Spain/epidemiology
16.
J Alzheimers Dis ; 66(4): 1397-1408, 2018.
Article in English | MEDLINE | ID: mdl-30400084

ABSTRACT

Amyloid-ß (Aß), a major component of senile plaques, is generated via the proteolysis of amyloid-ß protein precursor (AßPP). This cleavage also produces AßPP fragment-derived oligomers which can be highly neurotoxic. AßPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AßPP proteolysis (ß-secretase activity) and Aß clearance (Aß degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AßPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AßPP and secreted α-secretase-cleaved soluble AßPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Cathepsin B/metabolism , Free Radicals/metabolism , Oxidative Stress/physiology , Aging/metabolism , Brain/drug effects , Brain/metabolism , Cathepsin B/antagonists & inhibitors , Cell Line, Tumor , Dipeptides/pharmacology , Humans , Lysosomes/metabolism , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/drug effects
17.
Neurobiol Aging ; 68: 5-17, 2018 08.
Article in English | MEDLINE | ID: mdl-29689425

ABSTRACT

The causal agent(s) and molecular mechanisms of Alzheimer's disease (AD) remain unclear. Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) infection is involved in the AD pathogenesis. Oxidative stress (OS) may also be crucial in the AD development. Our group previously reported that both HSV-1 and OS trigger the appearance of AD-type neurodegeneration markers. The main aim of the present study was to identify the mechanisms involved in this triggering. Expression studies revealed the involvement of a set of OS-regulated genes in HSV-1-infected cells and in cells harboring the Swedish mutation of the amyloid beta precursor protein gene. Functional annotation of these genes revealed the lysosome system to be impaired, suggesting that the interaction of OS with both HSV-1 and amyloid beta precursor protein mutations affects lysosomal function. Functional studies revealed HSV-1 infection and OS to increase the lysosome load, reduce the activity of lysosomal hydrolases, affect cathepsin maturation, and inhibit the endocytosis-mediated degradation of the epidermal growth factor receptor. These findings suggest alterations in the lysosome system to be involved in different forms of AD.


Subject(s)
Herpes Simplex/complications , Herpes Simplex/genetics , Herpesvirus 1, Human , Lysosomes/pathology , Nerve Degeneration/etiology , Neurodegenerative Diseases/etiology , Oxidative Stress , Alzheimer Disease/etiology , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Humans , Lysosomes/genetics , Lysosomes/physiology , Mutation , Neurodegenerative Diseases/pathology , Tumor Cells, Cultured
18.
Neurosci Lett ; 408(3): 203-8, 2006 Nov 20.
Article in English | MEDLINE | ID: mdl-17014956

ABSTRACT

Alzheimer's disease (AD) is a complex multifactorial disorder involving a number of genetic and environmental factors, with severe head injury consistently reported as a major non-genetic risk factor. The adrenergic activation that occurs during major trauma increases cAMP levels, therefore the cAMP signaling pathway might be involved in AD pathogenesis. Time course of candidate gene expression following adrenergic stimulation with isoproterenol was assayed in neuroblastoma cells by quantitative reverse transcription (RT)-PCR. Then, genetic association studies of polymorphisms in several of these candidate genes were performed. Association studies in two independent case-control samples showed a polymorphism in DSC1, encoding desmocollin 1--a member of the desmosomal cadherins--which modulated AD susceptibility in a gender-specific manner. These results are in accordance with the potential involvement of the adrenergic signaling pathway in AD pathogenesis.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Alzheimer Disease/genetics , Desmocollins/genetics , Gene Expression Regulation/drug effects , Isoproterenol/pharmacology , Aged , Aged, 80 and over , Cell Line, Tumor , Female , Gene Expression Regulation/physiology , Gene Frequency , Genotype , Humans , Logistic Models , Male , Neuroblastoma , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Sex Factors , Time Factors
19.
J Alzheimers Dis ; 49(2): 343-52, 2016.
Article in English | MEDLINE | ID: mdl-26444794

ABSTRACT

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.


Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , tau Proteins/genetics , Aged , Aged, 80 and over , Apolipoprotein E4/genetics , Female , Frontotemporal Dementia/genetics , Haplotypes , Humans , Logistic Models , Male , Middle Aged , Spain
20.
Neuroreport ; 16(9): 1027-30, 2005 Jun 21.
Article in English | MEDLINE | ID: mdl-15931082

ABSTRACT

Systemic and local changes in apolipoprotein E (ApoE) quantity have been related with Alzheimer's and other neurodegenerative diseases, showing the relevance of maintaining physiological ApoE levels. However, APOE transcription has not been extensively studied in neural cells. In this report, we study the transcriptional activity of different APOE proximal promoter regions and their binding to nuclear proteins from human neural (astrocytoma and neuroblastoma) and peripheral (hepatoma and lymphoma) cell lines. We define several regions with a negative regulatory effect in all the cells and a region with a strong positive activity in neuroblastoma cells. Additionally, we show that the -219T/G polymorphism produces variations in APOE transcriptional activity, with the G allele showing higher activity.


Subject(s)
Apolipoproteins E/genetics , Gene Expression Regulation/physiology , Neurons/physiology , Promoter Regions, Genetic/physiology , Regulatory Sequences, Nucleic Acid/physiology , Cell Line, Tumor , Electrophoretic Mobility Shift Assay/methods , Humans , Neuroblastoma , Polymorphism, Genetic , Transcription, Genetic/physiology
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