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- Ewers, Michael, et al.
(författare)
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Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease.
- 2008
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 131:Pt 5, s. 1252-8
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Tidskriftsartikel (refereegranskat)abstract
- The Apolipoprotein (ApoE) epsilon 4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (A beta(1-42)). Recently, we have shown that beta-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of A beta(1-42), BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-epsilon 4 carriers and ApoE-epsilon 4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-epsilon 4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of A beta(1-42) were decreased in ApoE-epsilon 4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-epsilon 4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.
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- Schneider, Kara, et al.
(författare)
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Using reporters of different misfolded proteins reveals differential strategies in processing protein aggregates
- 2022
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 298:11
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of misfolded proteins is a hallmark of aging and many neurodegenerative diseases, making it important to understand how the cellular machinery recognizes and processes such proteins. A key question in this respect is whether misfolded proteins are handled in a similar way regardless of their genetic origin. To approach this question, we compared how three different misfolded proteins, guk1-7, gus1-3, and pro3-1, are handled by the cell. We show that all three are nontoxic, even though highly overexpressed, highlighting their usefulness in analyzing the cellular response to misfolding in the absence of severe stress. We found significant differences between the aggregation and disaggregation behavior of the misfolded proteins. Specifically, gus1-3 formed some aggregates that did not efficiently recruit the protein disaggregase Hsp104 and did not colocalize with the other misfolded reporter proteins. Strikingly, while all three misfolded proteins generally coaggregated and colocalized to specific sites in the cell, disaggregation was notably different; the rate of aggregate clearance of pro3-1 was faster than that of the other misfolded proteins, and its clearance rate was not hindered when pro3-1 colocalized with a slowly resolved misfolded protein. Finally, we observed using super-resolution light microscopy as well as immunogold labeling EM in which both showed an even distribution of the different misfolded proteins within an inclusion, suggesting that misfolding characteristics and remodeling, rather than spatial compartmentalization, allows for differential clearance of these misfolding reporters residing in the same inclusion. Taken together, our results highlight how properties of misfolded proteins can significantly affect processing.
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- Vanderstichele, Hugo, et al.
(författare)
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Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies.
- 2006
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Ingår i: Clinical chemistry and laboratory medicine : CCLM / FESCC. - 1434-6621. ; 44:12, s. 1472-80
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. METHODS: The analytical performance of the INNOTEST PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Abeta(1-42), for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. RESULTS: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.
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- Visser, Pieter Jelle, et al.
(författare)
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Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study.
- 2009
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Ingår i: Lancet neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 8:7, s. 619-27
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.
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