949 research outputs found
Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease
No full textSeveral studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD.
Williams J, Goate A
Factores modificadores de la edad de inicio del Alzheimer familiar por mutación (e280a de la ps-1)
No full textIP 1115-04-007-99Incluye anexosARTICULO(S) EN REVISTA: Factores modificadores de la edadde inicio de laenfermedad de alzheimer por;mutacion E280A de la presenilina-1 / Silvia Mejia, Francisco Lopera, DavidPineda, Alfredo Ardila, Sonia;Moreno, Liliana Cadavid. - En: Neuropsicologia, Neuropsiquiatriay Neurociencias vol. 1 No 2 p. 167-176. -;Cognitive decline in patients wite familial alzheimer's diseaseassociatedwith E280a presenilin-1 mutation: a;longitudinal study / Monica Rosselli, Alfredo Ardila, Sonia Moreno, Virginia Standish, Juan Carlos Arango;Lasprilla, Victoria Tirado, Jorge Ossa, Alison M. Goate, KennethS. Kosik,Francisco Lopera. - En: Journal of;Clinical and Experimental Neuropsychology vol. 22 No 4 (2000);p. 483-495.'- Age of onset in familial;alzheimer's disense: eduentional effects / Silvia Mejia, DavidPineda, Alfredo Ardila, M. Giraldo, Francisco;Lopera. - En: Journal of the International NeuropsychologicalSociety. - ISSN 13556177. - Alteraciones en el;SPECT cerebral antes del inicio de la enfermedad de alzheimerprecoz producida por la mutacion E280A de la PS1;/ Francisco Lopera, Isolda Siegert, Mauricio Arcos Burgos,Alejandro Rios.'- en: Acta Medica colombiana vol.;25 No 3 (2000 : may-jun); p. 144-149
Factores modificadores de la edad de inicio del Alzheimer familiar por mutación (e280a de la ps-1)
No full textIP 1115-04-007-99Incluye anexosARTICULO(S) EN REVISTA: Factores modificadores de la edadde inicio de laenfermedad de alzheimer por;mutacion E280A de la presenilina-1 / Silvia Mejia, Francisco Lopera, DavidPineda, Alfredo Ardila, Sonia;Moreno, Liliana Cadavid. - En: Neuropsicologia, Neuropsiquiatriay Neurociencias vol. 1 No 2 p. 167-176. -;Cognitive decline in patients wite familial alzheimer's diseaseassociatedwith E280a presenilin-1 mutation: a;longitudinal study / Monica Rosselli, Alfredo Ardila, Sonia Moreno, Virginia Standish, Juan Carlos Arango;Lasprilla, Victoria Tirado, Jorge Ossa, Alison M. Goate, KennethS. Kosik,Francisco Lopera. - En: Journal of;Clinical and Experimental Neuropsychology vol. 22 No 4 (2000);p. 483-495.'- Age of onset in familial;alzheimer's disense: eduentional effects / Silvia Mejia, DavidPineda, Alfredo Ardila, M. Giraldo, Francisco;Lopera. - En: Journal of the International NeuropsychologicalSociety. - ISSN 13556177. - Alteraciones en el;SPECT cerebral antes del inicio de la enfermedad de alzheimerprecoz producida por la mutacion E280A de la PS1;/ Francisco Lopera, Isolda Siegert, Mauricio Arcos Burgos,Alejandro Rios.'- en: Acta Medica colombiana vol.;25 No 3 (2000 : may-jun); p. 144-149
rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells from patients with Alzheimer's disease
No full textMutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 +/- 0.07 versus 1.73 +/- 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 +/- 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 +/- 0.23 versus 0.70 +/- 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 +/- 0.14, CC = 1.22 +/- 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival
An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells
No full textSummary: Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. We evaluated this protocol across 42 NPC lines (derived from 30 individuals). Transcriptomic analysis demonstrated that hiPSC-astrocytes from four individuals are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity, and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our protocol is a reproducible, straightforward (single medium), and rapid (<30 days) method to generate populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders. : Brennand, Goate, and colleagues report a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs) via a neural progenitor cell (NPC) intermediate. hiPSC-astrocytes resemble primary human fetal astrocytes, have a transcriptional signature consistent with a non-reactive state, respond to inflammatory stimulants, and enhance microglial phagocytosis. Keywords: human induced pluripotent stem cell, iPSC, astrocyt
A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
No full textPervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer’s disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders
Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition
No full textThere is substantial evidence that cerebrospinal fluid (CSF) levels of both Aβ42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Aβ and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Aβ42 levels were used to stratify the sample into those with and without likely Aβ deposition in the brain the association was only observed in individuals with evidence of Aβ deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Aβ deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Aβ deposition) interaction that places changes in CSF tau after Aβ deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression
SNPs in MAPT are associated with cerebrospinal fluid tau levels, MAPT mRNA levels, and age at onset of late-onset Alzheimer's disease
No full text
Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder
No full textALZHEIMER'S disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of tbe general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of pre-dominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors
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