@article{discovery10061211,
          number = {3},
            year = {2018},
           month = {November},
         journal = {Journal of Alzheimer's Disease},
           pages = {1053--1064},
            note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.},
           title = {Protofibrillar and Fibrillar Amyloid-{\ensuremath{\beta}} Binding Proteins in Cerebrospinal Fluid},
          volume = {66},
          author = {Rahman, MM and Westermark, GT and Zetterberg, H and H{\"a}rd, T and Sandgren, M},
        keywords = {Alzheimer's disease, amyloid-{\ensuremath{\beta}}, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils},
        abstract = {Aggregation and deposition of misfolded amyloid-{\ensuremath{\beta}} (A{\ensuremath{\beta}}) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of A{\ensuremath{\beta}} are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve A{\ensuremath{\beta}}-interacting molecular partners. In a previous study, we identified potential A{\ensuremath{\beta}}{$_4$}{$_2$} protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of A{\ensuremath{\beta}}{$_4$}{$_2$} (A{\ensuremath{\beta}}{$_4$}{$_2$}CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to A{\ensuremath{\beta}}{$_4$}{$_2$} fibrils in AD and non-AD CSF and compared these with protofibrillar A{\ensuremath{\beta}}{$_4$}{$_2$}CC-binding partners. A{\ensuremath{\beta}}{$_4$}{$_2$} fibrils sequestered 2.4-fold more proteins than A{\ensuremath{\beta}}{$_4$}{$_2$}CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar A{\ensuremath{\beta}}-binding proteins represent distinct functional categories. A{\ensuremath{\beta}}{$_4$}{$_2$}CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while A{\ensuremath{\beta}}{$_4$}{$_2$} 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 A{\ensuremath{\beta}} 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 A{\ensuremath{\beta}}-related toxicity mechanisms.},
             url = {http://dx.doi.org/10.3233/JAD-180596},
            issn = {1387-2877}
}