| 1. |
- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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| 2. |
- Sjölander, Annica, 1969
(författare)
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Alzheimer's Disease: effect of Tau-related genes on the pathology, neurochemistry and risk of disease
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's disease (AD) is the most common form of dementia in the elderly. The predominant sporadic form of AD is a genetically complex disorder probably involving a combination of genetic factors together with environmental influences. To date, the best established genetic risk factor identified is the APOE e4 allele. However not all AD cases have the APOE e4 allele, thus several susceptibility genes remain to be found. One of the characteristics of AD is the intraneuronal accumulation of neurofibrillary tangles (NFTs). NFTs are composed of a hyperphosphorylated form of the tau protein. Since tau pathology is a central and an important event in AD this thesis has focused on studying genes that are directly or indirectly related to tau and examine their effect on pathology, neurochemistry and risk of disease. In the first paper, we identified a single nucleotide polymorphism (SNP) in the cell division cycle (CDC2) gene. In AD brain, cdc2 is expressed in neurons and is involved in hyperphosphorylation of tau. The SNP was tested for association with sporadic AD. A significant association between both genotype and allele frequencies and AD was found. In next paper, we examined a SNP in the Saitohin (STH) gene, a gene located in on of the introns of the human TAU gene. Numerous SNPs span the human tau gene and are in complete linkage disequilibrium (LD) with each other yielding two separate haplotypes, H1 and H2. Patients with AD, FTD and PD and controls were genotyped for the STH SNP and/or the TAU haplotype. Genotype data were tested for their association to AD biomarkers in the cerebrospinal fluid (CSF) and to neuropathological scores of senile plaques. The STH SNP and the TAU haplotype were in complete LD in all patients (AD and FTD) and controls investigated for both genes. There were no significant differences in genotype or allele distributions in AD, FTD or PD patients compared to controls. Neither TAU haplotype nor STH influenced CSF biomarkers or neuropathological scores significantly. In next study, we followed up the findings from paper I and examined possible effects of the CDC2 SNP on CSF biomarkers and neuropathological scores in AD patients. The CDC2 I allele was associated with a gene dose-dependent increase of CSF total-tau levels. In conclusion, the results from paper I suggest a link between the CDC2 gene and AD. This is further supported by the findings from paper III, where we could provide evidence for an involvement of CDC2 in the pathogenesis of AD. We found no evidence that could support a major pathogenic role of STH and TAU haplotype in AD, FTD or PD in paper II.
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| 3. |
- Sjölander, Annica, 1969, et al.
(författare)
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Alzheimer's disease: No effect of the CDK5 gene on CSF biomarkers, neuropathology or disease risk
- 2009
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Ingår i: Molecular Medicine Reports. - : Spandidos Publications. - 1791-3004 .- 1791-2997. ; 2:6, s. 989-992
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin-dependent kinase 5 (cdk5) has been identified as one of the kinases that phosphorylates tau at several Alzheimer's disease (AD)-associated sites. Cdk5 is predominantly expressed in neurons, and has higher activity in AD brains than in non-demented brains. To investigate the effect of the CDK5 gene on AD, we analyzed an SNP of the CDK5 gene (rs2069456) in 347 patients with AD and in 157 controls. CDK5 genetic data was investigated in subgroups in relation to biochemical and neuropathological markers for AD. We found no significant differences in genotype or allele distributions between AD patients and controls. None of the CDK5 gene variants influenced biomarkers for AD.
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| 4. |
- Sjölander, Annica, 1969, et al.
(författare)
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The PPAR-alpha gene in Alzheimer's disease: lack of replication of earlier association.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:4, s. 666-8
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a single nucleotide polymorphism (SNP, rs1800206) in the peroxisome proliferator-activated receptor alpha (PPAR-alpha) gene has been proposed to be associated with Alzheimer's disease (AD). To verify this finding, we analyzed the PPAR-alpha SNP in 461 patients with AD and 1395 controls. In subgroups, PPAR-alpha gene data could be investigated in relation to biochemical and neuropathological markers for AD. We found no significant differences in genotype or allele distributions between AD patients and controls. None of the PPAR-alpha gene variants influenced markers for AD.
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