| 1. |
- Mattsson, Niklas, 1979, et al.
(författare)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 2. |
- Fritschi, Sarah K, et al.
(författare)
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Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid.
- 2014
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 137:11, s. 2909-2915
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Tidskriftsartikel (refereegranskat)abstract
- The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.
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| 3. |
- Heilbronner, Goetz, et al.
(författare)
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Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice
- 2013
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Ingår i: EMBO Reports. - : NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND. - 1469-221X .- 1469-3178. ; 14:11, s. 1017-1022
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Tidskriftsartikel (refereegranskat)abstract
- The polymorphic beta-amyloid lesions present in individuals with Alzheimers disease are collectively known as cerebral beta-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop beta-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and A beta 40/A beta 42 peptide ratio. To determine the nature of such beta-amyloid morphotypes, beta-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced beta-amyloid deposition with the morphological, conformational, and A beta 40/A beta 42 ratio characteristics of beta-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of beta-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced beta-amyloid deposits, although less prominent, and the induced deposits were similar to the beta-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated A beta in APP transgenic mice can be maintained by seeded conversion.
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| 4. |
- Kaeser, Stephan A., et al.
(författare)
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Cystatin C modulates cerebral beta-amyloidosis
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 39:12, s. 1437-1439
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Tidskriftsartikel (refereegranskat)abstract
- The CST3 Thr25 allele of CST3, which encodes cystatin C, leads to reduced cystatin C secretion and conveys susceptibility to Alzheimer's disease. Here we show that overexpression of human cystatin C in brains of APP-transgenic mice reduces cerebral amyloid-beta deposition and that cystatin C binds amyloid-beta and inhibits its fibril formation. Our results suggest that cystatin C concentrations modulate cerebral amyloidosis risk and provide an opportunity for genetic risk assessment and therapeutic interventions.
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| 5. |
- Novotny, Renata, et al.
(författare)
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Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model
- 2016
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Ingår i: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 36:18, s. 5084-5093
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.
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| 6. |
- Rasmussen, Jay, et al.
(författare)
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Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimers disease
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:49, s. 13018-13023
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Tidskriftsartikel (refereegranskat)abstract
- The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-beta peptide (A beta) has been shown to adopt distinct structural conformations with different biological activities, we asked whether A beta can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of beta-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimers disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of A beta nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to A beta plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic A beta-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic A beta among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between A beta conformation and clinical phenotype.
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