Protofibrillar and Fibrillar Amyloid-beta Binding Proteins in Cerebrospinal Fluid

Abstract

Aggregation and deposition of misfolded amyloid-beta (A beta) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of A beta are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve A beta-interacting molecular partners. In a previous study, we identified potential A beta(42) protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of A beta(42) (A beta 42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to A beta(42) fibrils in AD and non-AD CSF and compared these with protofibrillar A beta 42CC-binding partners. A beta(42) fibrils sequestered 2.4-fold more proteins than A beta 42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar A beta-binding proteins represent distinct functional categories. A beta 42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while A beta(42) 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 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 beta-related toxicity mechanisms.

Keywords

Alzheimer's disease; amyloid-beta; biomolecular interaction; cerebrospinal fluid; fibrils; protofibrils

Published in

Journal of Alzheimer's Disease
2018, volume: 66, number: 3, pages: 1053-1064
Publisher: IOS PRESS

SLU Authors

• Rahman, Mahafuzur

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    

• Härd, Torleif

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    

• Sandgren, Mats

  • Department of Molecular Sciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Neurosciences

Publication identifier

• DOI: https://doi.org/10.3233/JAD-180596

Permanent link to this page (URI)

https://res.slu.se/id/publ/97528