The Conformational Epitope for a New Aβ42 Protofibril-Selective Antibody Partially Overlaps with the Peptide N-Terminal Region

Benjamin A. Colvin; Victoria A. Rogers; Joshua A. Kulas; Elizabeth A. Ridgway; Fatima S. Amtashar; Colin K. Combs; Michael R. Nichols

doi:10.1111/jnc.14211

The Conformational Epitope for a New Aβ42 Protofibril-Selective Antibody Partially Overlaps with the Peptide N-Terminal Region

Benjamin A. Colvin, Victoria A. Rogers, Joshua A. Kulas, Elizabeth A. Ridgway, Fatima S. Amtashar, Colin K. Combs, Michael R. Nichols

University of Missouri-St. Louis

Research output: Contribution to journal › Article › peer-review

Abstract

<div class="line" id="line-7"> <span style='color: rgb(28, 29, 30); font-family: "Open Sans", icomoon, sans-serif; font-size: 16px;'> Aggregation and accumulation of amyloid&hyphen;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&hyphen;sheet structure. Our own  </span> <i style='color: rgb(28, 29, 30); font-family: "Open Sans", icomoon, sans-serif; font-size: 16px;'> in vitro  </i> <span style='color: rgb(28, 29, 30); font-family: "Open Sans", icomoon, sans-serif; font-size: 16px;'> 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&hyphen;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&hyphen;titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed AbSL , was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL 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 AbSL involved the N&hyphen;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. </span></div>

Original language	American English
Journal	Journal of Neurochemistry
Volume	143
DOIs	https://doi.org/10.1111/jnc.14211
State	Published - Dec 1 2017

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Biochemistry
Biology
Molecular Biology

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title = "The Conformational Epitope for a New Aβ42 Protofibril-Selective Antibody Partially Overlaps with the Peptide N-Terminal Region",

abstract = " Aggregation and accumulation of amyloid&hyphen;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&hyphen;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&hyphen;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&hyphen;titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed AbSL , was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL 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 AbSL involved the N&hyphen;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. ",

author = "Colvin, {Benjamin A.} and Rogers, {Victoria A.} and Kulas, {Joshua A.} and Ridgway, {Elizabeth A.} and Amtashar, {Fatima S.} and Combs, {Colin K.} and Nichols, {Michael R.}",

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doi = "10.1111/jnc.14211",

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T1 - The Conformational Epitope for a New Aβ42 Protofibril-Selective Antibody Partially Overlaps with the Peptide N-Terminal Region

AU - Colvin, Benjamin A.

AU - Rogers, Victoria A.

AU - Kulas, Joshua A.

AU - Ridgway, Elizabeth A.

AU - Amtashar, Fatima S.

AU - Combs, Colin K.

AU - Nichols, Michael R.

N1 - Enter your email address below. If your address has been previously registered, you will receive an email with instructions on how to reset your password. If you don't receive an email, you should register as a new user

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Aggregation and accumulation of amyloid&hyphen;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&hyphen;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&hyphen;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&hyphen;titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed AbSL , was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL 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 AbSL involved the N&hyphen;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.

AB - Aggregation and accumulation of amyloid&hyphen;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&hyphen;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&hyphen;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&hyphen;titer anti serum with a strong affinity for Aβ42 protofibrils. The antiserum, termed AbSL , was selective for Aβ42 protofibrils over Aβ42 monomers and Aβ42 fibrils. AbSL 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 AbSL involved the N&hyphen;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.

UR - http://onlinelibrary.wiley.com/doi/10.1111/jnc.14211/full

U2 - 10.1111/jnc.14211

DO - 10.1111/jnc.14211

M3 - Article

VL - 143

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

ER -

The Conformational Epitope for a New Aβ42 Protofibril-Selective Antibody Partially Overlaps with the Peptide N-Terminal Region

Abstract

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