eprintid: 10061211 rev_number: 23 eprint_status: archive userid: 608 dir: disk0/10/06/12/11 datestamp: 2018-11-12 14:55:48 lastmod: 2021-09-17 22:10:14 status_changed: 2019-02-01 17:10:36 type: article metadata_visibility: show creators_name: Rahman, MM creators_name: Westermark, GT creators_name: Zetterberg, H creators_name: Härd, T creators_name: Sandgren, M title: Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: Alzheimer’s disease, amyloid-β, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. 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. date: 2018-11-23 date_type: published official_url: http://dx.doi.org/10.3233/JAD-180596 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1598926 doi: 10.3233/JAD-180596 pii: JAD180596 lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Zetterberg, Henrik actors_name: Harriot, Anne-Marie actors_id: HZETT94 actors_id: AHARA72 actors_role: owner actors_role: impersonator full_text_status: public publication: Journal of Alzheimer's Disease volume: 66 number: 3 pagerange: 1053-1064 event_location: Netherlands issn: 1387-2877 citation: 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 <https://doi.org/10.3233/JAD-180596>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10061211/1/Zetterberg_Protofibrillar%20and%20Fibrillar%20Amyloid-%CE%B2%20Binding%20Proteins%20in%20Cerebrospinal%20Fluid_AAM.pdf