| 1. |
- Ingelsson, Martin, et al.
(author)
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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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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 112:4, s. 439-449
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Journal article (peer-reviewed)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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| 2. |
- Blom, Elin S., et al.
(author)
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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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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 27:5, s. 458-64
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Journal article (peer-reviewed)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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| 3. |
- Giedraitis, Vilmantas, et al.
(author)
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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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In: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 427:3, s. 127-131
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Journal article (peer-reviewed)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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| 4. |
- Ingelsson, Martin, et al.
(author)
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Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains
- 2007
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 114:5, s. 471-479
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Journal article (peer-reviewed)abstract
- Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.
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| 5. |
- Matsui, Toshifumi, et al.
(author)
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Expression of APP pathway mRNAs and proteins in Alzheimer's disease
- 2007
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In: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1161, s. 116-123
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Journal article (peer-reviewed)abstract
- In both trisomy 21 and rare cases of triplication of amyloid precursor protein (APP) Alzheimer's disease (AD) pathological changes are believed to be secondary to increased expression of APP. We hypothesized that sporadic AD may also be associated with changes in transcription of APP or its metabolic partners. To address this issue, temporal neocortex of 27 AD and 21 non-demented control brains was examined to assess mRNA levels of APP isoforms (total APP, APP containing the Kunitz protease inhibitor domain [APP-KPI] and APP770) and APP metabolic enzymatic partners (the APP cleaving enzymes beta-secretase [BACE] and presenilin-1 [PS- 1], and putative clearance molecules, low-density lipoprotein receptor protein [LRP] and apolipoprotein E [apoE]). Furthermore, we evaluated how changes in APP at the mRNA level affect the amount of Tris buffer extractable APP protein and A beta 40 and 42 peptides in AD and control brains. As assessed by quantitative PCR, APP-KPI (p=0.007), APP770 (p=0.004), PS-1 (p = 0.004), LRP (p = 0.003), apoE (p = 0.0002) and GFAP (p < 0.0001) mRNA levels all increased in AD, and there was a shift from APP695 (a neuronal isoform) towards KPI containing isoforms that are present in glia as well. APP-KPI mRNA levels correlated with soluble APP alpha -KPI protein (sAPP alpha -KPI) levels measured by ELISA (T= 0.33, p = 0.015 by Kendall's rank correlation); in turn, soluble APP alpha-KPI protein levels positively correlated with Tris -extractable, soluble A beta 40 (p=0.046) and 42 levels (p=0.007). The ratio of soluble APP alpha-KPI protein levels to total APP protein increased in AD, and also correlated with GFAP protein levels in AD. These results suggest that altered transcription of APP in AD is proportionately associated with A beta peptide, may occur in the context of gliosis, and may contribute to A beta deposition in sporadic AD.
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| 6. |
- Sundelöf, Johan, et al.
(author)
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Plasma β Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men : A Prospective, Population-Based Cohort Study
- 2008
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In: Archives of Neurology. - : American Medical Association (AMA). - 0003-9942 .- 1538-3687. ; 65:2, s. 256-63
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Journal article (peer-reviewed)abstract
- BACKGROUND: Beta amyloid (Abeta) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma. OBJECTIVE: To examine plasma levels of Abeta peptides Abeta(40) and Abeta(42) as predictors of incident AD and other types of dementia. DESIGN: Prospective, population-based cohort study. SETTING: The Uppsala Longitudinal Study of Adult Men. PARTICIPANTS: Plasma Abeta(40) and Abeta(42) levels were analyzed as predictors of incident AD in 1045 men at age 70 years and 680 men at age 77 years using Cox proportional hazards analyses. Alzheimer disease and other types of dementia were diagnosed by standardized screening, clinical evaluation, and medical record review. MAIN OUTCOME MEASURES: Hazard ratios of AD (primary outcome) and vascular dementia or other dementia (secondary outcomes) according to baseline levels of plasma Abeta(40) and Abeta(42). RESULTS: From the age of 77 years at baseline, 46 individuals developed AD at follow-up (median, 5.3 years). A low plasma Abeta(40) level at age 77 years was associated with higher incidence of AD. The multivariate-adjusted hazard ratio was 4.87 (95% confidence interval, 1.63-14.6) for the lowest Abeta(40) tertile compared with the highest tertile. On follow-up from age 70 years at baseline (median, 11.2 years), 82 individuals developed AD. Plasma Abeta(40) and Abeta(42) levels measured at age 70 years were not significantly associated with incident AD. CONCLUSIONS: Low plasma Abeta(40) levels predicted incident AD in elderly men independently of potential confounders. Plasma Abeta(42) levels were not significantly associated with AD incidence. The clinical value of Abeta measurement in plasma remains to be established in future studies.
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