| 1. |
- Blom, Elin S, et al.
(författare)
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Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain
- 2010
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252 .- 2090-8024. ; 2011, s. 936580-
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Tidskriftsartikel (refereegranskat)abstract
- Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.
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| 2. |
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| 3. |
- Blom, Elin S., et al.
(författare)
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Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype.
- 2009
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 27:5, s. 458-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Increased cerebrospinal fluid (CSF) tau, decreased CSF amyloid-beta42 (Abeta42) and the apolipoprotein E gene (APOE) epsilon4 allele predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Here, we investigated these markers to assess their predictive value and influence on the rate of disease progression. METHODS: Using ELISA, we measured the CSF biomarkers in 47 AD patients, 58 patients with MCI and 35 healthy control subjects. Twenty-eight MCI patients revisited the clinic and half of them progressed to AD during a period of 3-12 years. RESULTS: The expected changes in CSF total (T)-tau, phosphorylated (P)-tau and Abeta42 levels were found in AD, confirming the diagnostic value of these biomarkers. We were also able to corroborate an increased risk for progression from MCI to AD with elevated CSF T-tau and P-tau and with the presence of the APOE epsilon4/epsilon4 genotype, but not with decreased Abeta42. Finally, for the first time we demonstrated that MCI subjects with high CSF T-tau or P-tau and APOE epsilon4 homozygosity progressed faster from MCI to AD. CONCLUSIONS: CSF T-tau and P-tau as well as the APOE epsilon4/epsilon4 genotype are robust predictors of AD and are also associated with a more rapid progression from MCI to AD.
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| 4. |
- Giedraitis, Vilmantas, et al.
(författare)
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The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease
- 2007
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 427:3, s. 127-131
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (A beta) with 40 (A beta 40) and 42 (A beta 42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF A beta 42 is decreased in AD, some studies have reported changed plasma A beta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of A beta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma A beta. We have measured A beta 40 and A beta 42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n= 18). We observed a clear correlation between CSF and plasma levels for both A beta 40 and A beta 42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of A beta 42 in AD CSF, whereas there were no significant differences in plasma A beta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma A beta may be disrupted with the initiation of amyloid deposition in the brain.
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| 5. |
- O'Callaghan, Paul, et al.
(författare)
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Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells
- 2008
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 18:4, s. 548-561
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta-peptide (Abeta) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in Abeta deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with Abeta plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the Abeta40 dense cores of neuritic plaques, but was largely absent from diffuse Abeta42 plaques, suggesting that Abeta42 deposition may occur independently of HS. A codeposition pattern of HS with Abeta deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with Abeta deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following Abeta stimulation. These results suggest that HS codeposits with Abeta40 in neuritic plaques and is mainly derived from glial cells.
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| 6. |
- Philipson, Ola, et al.
(författare)
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A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:9, s. 1393-405
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.
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| 7. |
- Gyorgy, Bence, et al.
(författare)
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CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer's Disease
- 2018
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Ingår i: Molecular Therapy Nucleic Acids. - : CELL PRESS. - 2162-2531. ; 11, s. 429-440
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Tidskriftsartikel (refereegranskat)abstract
- The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer's disease (AD) as a result of increased beta-secretase cleavage of the amyloid-beta (A beta) precursor protein. This leads to abnormally high A beta levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APP(sw) allele using CRISPR. By applying CRISPR/Cas9 from Streptococcus pyogenes, we generated allele-specific deletions of either APP(sw) or APP(WT). As measured by ELISA, conditioned media of targeted patient-derived fibroblasts displayed an approximate 60% reduction in secreted A beta. Next, coding sequences for the APP(sw)-specific guide RNA (gRNA) and Cas9 were packaged into separate adeno-associated viral (AAV) vectors. Site-specific indel formation was achieved both in primary neurons isolated from APP(sw) transgenic mouse embryos (Tg2576) and after co-injection of these vectors into hippocampus of adult mice. Taken together, we here present proof-of-concept data that CRISPR/Cas9 can selectively disrupt the APP(sw) allele both ex vivo and in vivo-and thereby decrease pathogenic A beta. Hence, this system may have the potential to be developed as a tool for gene therapy against AD caused by APPswe and other point mutations associated with increased A beta.
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| 8. |
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| 9. |
- Ingelsson, Martin, et al.
(författare)
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No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain
- 2006
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 112:4, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.
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| 10. |
- Skoglund, Lena, et al.
(författare)
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Novel Progranulin Mutation Detected in 2 Patients With FTLD
- 2011
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Ingår i: Alzheimer Disease and Associated Disorders. - : Lippincott Williams & Wilkins. - 0893-0341 .- 1546-4156. ; 25:2, s. 173-178
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense-mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic.
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