TY  - JOUR
ID  - discovery10061211
N2  - Aggregation and deposition of misfolded amyloid-? (A?) peptide in the brain is central to Alzheimer?s disease (AD). Oligomeric, protofibrillar, and fibrillar forms of A? are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve A?-interacting molecular partners. In a previous study, we identified potential A??? protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of A??? (A???CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to A??? fibrils in AD and non-AD CSF and compared these with protofibrillar A???CC-binding partners. A??? fibrils sequestered 2.4-fold more proteins than A???CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar A?-binding proteins represent distinct functional categories. A???CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while A??? 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? 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?-related toxicity mechanisms.
KW  - Alzheimer?s disease
KW  -  amyloid-?
KW  -  biomolecular interaction
KW  -  cerebrospinal fluid
KW  -  fibrils
KW  -  protofibrils
TI  - Protofibrillar and Fibrillar Amyloid-? Binding Proteins in Cerebrospinal Fluid
EP  - 1064
AV  - public
Y1  - 2018/11/23/
SN  - 1387-2877
UR  - http://dx.doi.org/10.3233/JAD-180596
JF  - Journal of Alzheimer's Disease
A1  - Rahman, MM
A1  - Westermark, GT
A1  - Zetterberg, H
A1  - Härd, T
A1  - Sandgren, M
VL  - 66
SP  - 1053
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
IS  - 3
ER  -