| 1. |
- Gkanatsiou, Eleni, et al.
(författare)
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A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer's disease.
- 2019
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Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 701, s. 125-131
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid angiopathy (CAA) is a type of vascular disease present in more than 50% of demented elderly and more than 80% of Alzheimer's disease (AD) patients. Both CAA and AD are characterized by extracellular Aβ deposits with the distinction that CAA has vascular deposits while AD has amyloid plaques. In this study, we used immunoprecipitation (IP) in combination with mass spectrometry (MS) to test the hypothesis that the Aβ peptide pattern differs between subjects having Aβ plaque pathology only and subjects with Aβ plaque pathology together with CAA pathology. Occipital lobes from 12 AD brains, ranging from no CAA to severe CAA, were extracted using 70% formic acid followed by IP-MS analysis. The Aβ peptide pattern differed greatly between subjects with no CAA compared to subjects with CAA. In cases with CAA, the most abundant Aβ peptides ended at amino acid 40 including Aβ1-40 (P=.048) and Aβ 2-40 (P=.0253) which were significantly increased compared to cases with no CAA. This was in contrast to subjects with no CAA where the most abundant Aβ peptides ended at amino acid 42 of which Aβ1-42 (P=.0101) and Aβ2-42 (P=.0051) as well as the pyroglutamate (pGlu)-modified peptides pGlu Aβ3-42 (P=.0177), and pGlu Aβ11-42 (P=.0088) were significantly increased compared to CAA subjects. The results are in line with earlier immunohistochemistry data and show that the molecular composition of the Aβ deposits found in blood vessels are different to the parenchymal deposits, suggesting they arise from distinct pathogenic pathways. This information may be useful in the development of pathology-specific biomarkers.
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| 2. |
- Lantero Rodriguez, Juan, et al.
(författare)
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P-tau235: a novel biomarker for staging preclinical Alzheimer's disease.
- 2021
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Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.
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| 3. |
- Nazir, Faisal Hayat, et al.
(författare)
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Molecular forms of neurogranin in cerebrospinal fluid.
- 2021
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 157:3, s. 816-833
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Tidskriftsartikel (refereegranskat)abstract
- Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally important domain, yielding the majority of fragments identified in cerebrospinal fluid (CSF), suggesting that cleavage of Ng may be a mechanism to regulate its function. Up to now, Ng has been shown to be present in CSF as both C-terminal fragments as well as full-length protein. To obtain an overview of the different molecular forms of Ng present in CSF, we show by size exclusion chromatography (SEC), immunoblotting, immunoprecipitation and MS that Ng is present in CSF as several molecular forms. Besides monomeric full-length Ng, also higher molecular weight forms of Ng, and C-terminal- and previously not identified N-terminal fragments were observed. We found by immunodepletion that C-terminal peptides contribute on average to ~50 % of the total-Ng ELISA signal in CSF samples. There were no differences in the overall C-terminal fragment/total-Ng ratio between samples from AD and control groups. In addition, we found that monomeric Ng and its C-terminal fragments bind to heparin via a heparin-binding motif, which might be of relevance for their export mechanism from neurons. Taken together, this study highlights the presence of several molecular forms of Ng in CSF, comprising monomeric full-length Ng, and N- and C-terminal truncations of Ng, as well as larger forms of still unknown composition.
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