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1.
J Geriatr Psychiatry Neurol ; 31(2): 90-96, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29562810

RESUMEN

BACKGROUND: Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD. METHODS: A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study. RESULTS: Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender. CONCLUSION: Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.


Asunto(s)
Edad de Inicio , Enfermedad de Alzheimer/genética , Técnicas de Genotipaje/métodos , Mutación , Proproteína Convertasa 9/genética , Enfermedad de Alzheimer/patología , LDL-Colesterol/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9/sangre , Factores de Riesgo
2.
Alzheimers Dement ; 14(6): 787-796, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29360470

RESUMEN

INTRODUCTION: Because currently known Alzheimer's disease (AD) single-nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD. METHODS: Our team performed a genome-wide association study in the Quebec Founder Population isolate to identify novel protective or risk genetic factors for late-onset sporadic AD and examined the impact of these variants on gene expression and AD pathology. RESULTS: The rs10984186 variant is associated with an increased risk of developing AD and with a higher CDK5RAP2 mRNA prevalence in the hippocampus. On the other hand, the rs4837766 variant, which is among the best cis-expression quantitative trait loci in the CDK5RAP2 gene, is associated with lower mild cognitive impairment/AD risk and conversion rate. DISCUSSION: The rs10984186 risk and rs4837766 protective polymorphic variants of the CDK5RAP2 gene might act as potent genetic modifiers for AD risk and/or conversion by modulating the expression of this gene.


Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas del Tejido Nervioso/genética , Proteínas tau/metabolismo , Anciano , Enfermedad de Alzheimer/patología , Proteínas de Ciclo Celular , Disfunción Cognitiva/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipocampo/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
3.
Eur J Neurosci ; 30(9): 1823-30, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19863653

RESUMEN

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.


Asunto(s)
Enfermedad de Alzheimer , Arildialquilfosfatasa/genética , Variación Genética , Polimorfismo de Nucleótido Simple , Anciano , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Encéfalo/patología , Colina O-Acetiltransferasa/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino
4.
J Alzheimers Dis ; 63(4): 1547-1556, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29782315

RESUMEN

One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.


Asunto(s)
Enfermedad de Alzheimer , Citocinas/metabolismo , Hipocampo/lesiones , Hipocampo/fisiopatología , Receptor Toll-Like 4/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Estudios de Casos y Controles , Cerebelo/metabolismo , Cerebelo/patología , Estudios de Cohortes , Citocinas/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Receptor Toll-Like 4/genética
5.
Neurobiol Aging ; 66: 180.e1-180.e9, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29503034

RESUMEN

Genome-wide association studies have identified several cholesterol metabolism-related genes as top risk factors for late-onset Alzheimer's disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Colesterol/metabolismo , Estudio de Asociación del Genoma Completo , Polimorfismo Genético , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Lóbulo Frontal/metabolismo , Expresión Génica , Sitios Genéticos/genética , Humanos , Placa Amiloide/líquido cefalorraquídeo , Factores de Riesgo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteínas tau/líquido cefalorraquídeo
6.
Neurobiol Aging ; 65: 132-139, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29476987

RESUMEN

The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP)ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i.e., protein tau phosphorylated) production in the brain. In this study, a significant positive correlation was observed between the synthases mRNA prevalence and disease status (FPPS, p < 0.001, n = 123; GGPPS, p < 0.001, n = 122). The levels of mRNA for hFPPS and hGGPPS were found to significantly correlate with the amount of p-Tau protein levels (p < 0.05, n = 34) and neurofibrillary tangle density (p < 0.05, n = 39) in the frontal cortex. Interestingly, high levels of hFPPS and hGGPPS mRNA prevalence are associated with earlier age of onset in AD (p < 0.05, n = 58). Together, these results suggest that accumulation of p-Tau in the AD brain is related, at least in part, to increased levels of neuronal isoprenoids.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Cerebelo/metabolismo , Cerebelo/patología , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Terpenos/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Farnesiltransferasa/fisiología , Femenino , Geraniltranstransferasa/fisiología , Humanos , Masculino , Ácido Mevalónico/metabolismo , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Fosfatos de Poliisoprenilo/biosíntesis , Prenilación de Proteína , Sesquiterpenos , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
7.
J Mol Neurosci ; 58(1): 109-19, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26541602

RESUMEN

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.


Asunto(s)
Enfermedad de Alzheimer/genética , Hidroximetilglutaril-CoA Reductasas/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Cerebelo/metabolismo , Cerebelo/patología , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
8.
J Alzheimers Dis ; 54(3): 913-922, 2016 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-27567841

RESUMEN

BACKGROUND: Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer's disease (AD) susceptibility genes with distinct pharmacogenomic properties. OBJECTIVE: To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects. METHODS: Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer's Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects. RESULTS: Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder's pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects. CONCLUSIONS: APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Butirilcolinesterasa/genética , Inhibidores de la Colinesterasa/uso terapéutico , Disfunción Cognitiva/genética , Indanos/uso terapéutico , Piperidinas/uso terapéutico , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/epidemiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/epidemiología , Progresión de la Enfermedad , Donepezilo , Método Doble Ciego , Femenino , Humanos , Masculino , Quebec/epidemiología , Resultado del Tratamiento
9.
Neurobiol Aging ; 35 Suppl 2: S3-10, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24973118

RESUMEN

The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1-42 concentrations without significant modifications of lipid hydroperoxide levels.


Asunto(s)
Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/etiología , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/uso terapéutico , Apolipoproteína E4/genética , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Homeostasis , Metabolismo de los Lípidos , Probucol/farmacología , Probucol/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/líquido cefalorraquídeo , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación/efectos de los fármacos , Proteínas tau/líquido cefalorraquídeo
10.
Brain Res ; 1562: 39-51, 2014 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-24661912

RESUMEN

Entorhinal cortex lesioning (ECL) causes an extensive deafferentation of the hippocampus that is classically followed by a compensatory reinnervation, where apolipoprotein E, the main extracellular lipid-carrier in the CNS, has been shown to play a crucial role by shuttling cholesterol to reconstructing neurons terminals. Hence, we investigated whether the ATP-binding cassette (ABC) transporters -A1 and -G1, known to regulate cellular cholesterol efflux and lipidation of the apolipoprotein E-containing lipoprotein complex are actively involved in this context of brain׳s plastic response to neurodegeneration and deafferentation. We assessed ABCA1 and ABCG1 mRNA and protein levels throughout the degenerative phase and the reinnervation process and evaluated the associated cholinergic sprouting following ECL in the adult mouse brain. We subsequently tested the effect of the pharmacological activation of the nuclear receptor LXR, prior to versus after ECL, on hippocampal ABCA1 and G1 expression and on reinnervation. ECL induced a time-dependent up-regulation of ABCA1, but not G1, that coincided with a significant increase in acetylcholine esterase (AChE) activity in the ipsilateral hippocampus. Pre-ECL, but not post-ECL i.p. treatment with the LXR agonist TO901317 also led to a significant increase solely in hippocampal ABCA1 expression, paralleled by increases in both AchE and synaptophysin protein levels in the deafferented hippocampus. Thus, ABCA1 and -G1 are differentially regulated in the lesioned brain and upon treatment with an LXR agonist. Further, TO901317-induced up-regulation of ABCA1 appears to be more beneficial in a prevention (pre-lesion) than rescue (post-lesion) treatment; both findings support a central role for ABC transporters in brain plasticity.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Corteza Entorrinal/lesiones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lipoproteínas/genética , Receptores Nucleares Huérfanos/agonistas , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Lateralidad Funcional , Proteínas Ligadas a GPI/metabolismo , Expresión Génica/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiología , Hidrocarburos Fluorados/farmacología , Lipoproteínas/metabolismo , Receptores X del Hígado , Masculino , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores Nucleares Huérfanos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfonamidas/farmacología , Sinaptofisina/metabolismo , Factores de Tiempo
11.
J Lipid Res ; 49(6): 1254-67, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18314463

RESUMEN

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Abeta production. To clarify the in vivo roles of ABCG1 in Abeta metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Abeta, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Abeta levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Abeta metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/fisiología , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Colesterol/biosíntesis , Lipoproteínas/fisiología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Animales , Secuencia de Bases , Transporte Biológico , Células Cultivadas , Cartilla de ADN , Proteínas de Unión al ADN/metabolismo , Receptores X del Hígado , Ratones , Receptores Nucleares Huérfanos , Receptores Citoplasmáticos y Nucleares/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
12.
Eur J Neurosci ; 24(5): 1245-51, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16965549

RESUMEN

Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Lipoproteína Lipasa/genética , Polimorfismo Genético , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Análisis de Varianza , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Química Encefálica , Canadá/epidemiología , Estudios de Casos y Controles , Colesterol/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Ovillos Neurofibrilares/patología , Pruebas Neuropsicológicas , Oportunidad Relativa , Placa Amiloide/patología , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
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