Rahman, MM;
Westermark, GT;
Zetterberg, H;
Härd, T;
Sandgren, M;
(2018)
Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid.
Journal of Alzheimer's Disease
, 66
(3)
pp. 1053-1064.
10.3233/JAD-180596.
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Abstract
Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer’s disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ₄₂ protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ₄₂ (Aβ₄₂CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ₄₂ fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ₄₂CC-binding partners. Aβ₄₂ fibrils sequestered 2.4-fold more proteins than Aβ₄₂CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ₄₂CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ₄₂ fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms.
| Type: | Article |
|---|---|
| Title: | Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3233/JAD-180596 |
| Publisher version: | http://dx.doi.org/10.3233/JAD-180596 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Alzheimer’s disease, amyloid-β, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10061211 |
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