| 1. |
- Laitera, Tiina, et al.
(författare)
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The Expression of Transthyretin and Amyloid-beta Protein Precursor is Altered in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:4, s. 959-968
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer's disease (AD)related amyloid-beta (A beta) plaques are frequently observed in the neocortex. iNPH patients with prominent A beta pathology show AD-related alterations in amyloid-beta protein precursor (A beta PP) processing resulting from increased gamma-secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of similar to 35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sA beta PP alpha, sA beta PP beta, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and A beta PP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A beta PP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of beta-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sA beta PP alpha and sA beta PP beta, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.
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| 2. |
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| 3. |
- Martiskainen, Henna, et al.
(författare)
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Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models
- 2015
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 36:2, s. 1221e15-1221e28
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.
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| 4. |
- Kämäläinen, Anna, et al.
(författare)
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GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients.
- 2013
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 33:1, s. 23-7
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.
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| 5. |
- Natunen, Teemu, et al.
(författare)
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Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor alpha and the Progression of Alzheimer's Disease
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e80700-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) has been postulated to involve defects in the clearance of amyloid-beta (A beta). Activation of liver X receptor alpha (LXR alpha) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of A beta. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXR alpha reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1. We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE epsilon 4 allele increased soluble A beta 42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble A beta 42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXR alpha and the levels of soluble A beta 42.
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| 6. |
- Natunen, Teemu, et al.
(författare)
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Elucidation of the BACE1 Regulating Factor GGA3 in Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 37:1, s. 217-232
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Tidskriftsartikel (refereegranskat)abstract
- Golgi-localized gamma-ear-containing ADP-ribosylation factor-binding protein (GGA3) is a central regulator of trafficking and degradation of BACE1 (beta-site A beta PP-cleaving enzyme), the rate-limiting enzyme in the production of amyloid-beta (A beta) in Alzheimer's disease (AD). Here, we assessed the potential role of GGA3 in AD pathogenesis using independent neuropathological, case-control, and family-based human sample cohorts. Increased BACE1 levels coincided with decreased GGA3 levels and with elevated phosphorylation status of eIF2 alpha-Ser51 in the temporal cortex of AD patients as compared to age-matched controls. Severity of the disease did not alter mRNA or protein levels of GGA3 in the inferior temporal cortex of AD patients, while a positive correlation between GGA3 and the levels of total, but not phosphorylated, tau was observed. Genetically, we did not observe consistent evidence for association between AD risk and common GGA3 polymorphisms across a number of independent sample cohorts. However, a nominally significant association was observed with rs2242230 (p < 0.05) among the Finnish case-control cohort. Accordingly, mRNA and protein levels of GGA3 in the inferior temporal cortex of AD patients did not significantly correlate with rs2242230 genotype status. While the present study indicates that GGA3 is involved in the cellular processes relevant for AD pathogenesis, the genetic data do not support the idea that common GGA3 polymorphisms would contribute to AD risk.
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