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The conformational epitope for a new Aβ42 protofibril‐selective antibody partially overlaps with the peptide N‐terminal region
Author(s) -
Colvin Benjamin A.,
Rogers Victoria A.,
Kulas Joshua A.,
Ridgway Elizabeth A.,
Amtashar Fatima S.,
Combs Colin K.,
Nichols Michael R.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14211
Subject(s) - epitope , fibril , antibody , chemistry , peptide , microglia , in vitro , biochemistry , microbiology and biotechnology , biophysics , biology , inflammation , immunology
Aggregation and accumulation of amyloid‐β peptide (Aβ) is a key component of Alzheimer's disease ( AD ). While monomeric Aβ appears to be benign, oligomers adopt a biologically detrimental structure. These soluble structures can be detected in AD brain tissue by antibodies that demonstrate selectivity for aggregated Aβ. Protofibrils are a subset of soluble oligomeric Aβ species and are described as small (< 100 nm) curvilinear assemblies enriched in β‐sheet structure. Our own in vitro studies demonstrate that microglial cells are much more sensitive to soluble Aβ42 protofibrils compared to Aβ42 monomer or insoluble Aβ42 fibrils. Protofibrils interact with microglia, trigger Toll‐like receptor signaling, elicit cytokine transcription and expression, and are rapidly taken up by the cells. Because of the importance of this Aβ species, we sought to develop an antibody that selectively recognizes protofibrils over other Aβ species. Immunization of rabbits with isolated Aβ42 protofibrils generated a high‐titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed Ab SL , was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. Ab SL did not react with amyloid precursor protein and recognized distinct pathological features in AD transgenic mouse brain slices. Competition studies with an Aβ antibody that targets residues 1–16 indicated that the conformational epitope for Ab SL involved the N‐terminal region of protofibrils in some manner. The newly developed antibody may have potential diagnostic and therapeutic uses in AD tissue and patients, and targeting of protofibrils in AD may have beneficial effects. Read the Editorial Highlight for this article on page 621. Cover Image for this issue: doi. 10.1111/jnc.13827 .