| 1. |
- Giedraitis, Vilmantas, et al.
(författare)
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CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid
- 2010
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 469:2, s. 265-267
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.
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| 2. |
- Laiterä, Tiina, et al.
(författare)
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Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
- 2017
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 55:3, s. 995-1003
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.
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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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