N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody
Abstract Background The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated py...
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ftsubgoettingen:oai:goescholar:1/12500 2023-05-15T15:17:35+02:00 N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody Antonios, Gregory Saiepour, Nasrin Bouter, Yvonne Richard, Bernhard C. Paetau, Anders Verkkoniemi-Ahola, Auli Lannfelt, Lars Ingelsson, Martin Kovacs, Gabor G. Pillot, Thierry Wirths, Oliver Bayer, Thomas A. 2013 http://resolver.sub.uni-goettingen.de/purl?gs-1/12500 https://doi.org/10.1186/2051-5960-1-56 eng eng http://resolver.sub.uni-goettingen.de/purl?gs-1/12500 Acta Neuropathologica Communications. 2013 Sep 06;1(1):56 doi:10.1186/2051-5960-1-56 24252153 openAccess http://creativecommons.org/licenses/by/2.0/ Antonios et al.; licensee BioMed Central Ltd. CC-BY journalArticle publishedVersion 2013 ftsubgoettingen https://doi.org/10.1186/2051-5960-1-56 2022-11-02T09:28:37Z Abstract Background The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology. Results Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD. Conclusions Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research. peerReviewed Article in Journal/Newspaper Arctic Georg-August-Universität Göttingen: GoeScholar Arctic Acta Neuropathologica Communications 1 1 56 |
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Georg-August-Universität Göttingen: GoeScholar |
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English |
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Abstract Background The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology. Results Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD. Conclusions Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research. peerReviewed |
format |
Article in Journal/Newspaper |
author |
Antonios, Gregory Saiepour, Nasrin Bouter, Yvonne Richard, Bernhard C. Paetau, Anders Verkkoniemi-Ahola, Auli Lannfelt, Lars Ingelsson, Martin Kovacs, Gabor G. Pillot, Thierry Wirths, Oliver Bayer, Thomas A. |
spellingShingle |
Antonios, Gregory Saiepour, Nasrin Bouter, Yvonne Richard, Bernhard C. Paetau, Anders Verkkoniemi-Ahola, Auli Lannfelt, Lars Ingelsson, Martin Kovacs, Gabor G. Pillot, Thierry Wirths, Oliver Bayer, Thomas A. N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
author_facet |
Antonios, Gregory Saiepour, Nasrin Bouter, Yvonne Richard, Bernhard C. Paetau, Anders Verkkoniemi-Ahola, Auli Lannfelt, Lars Ingelsson, Martin Kovacs, Gabor G. Pillot, Thierry Wirths, Oliver Bayer, Thomas A. |
author_sort |
Antonios, Gregory |
title |
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
title_short |
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
title_full |
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
title_fullStr |
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
title_full_unstemmed |
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody |
title_sort |
n-truncated abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using nt4x-167, a novel monoclonal antibody |
publishDate |
2013 |
url |
http://resolver.sub.uni-goettingen.de/purl?gs-1/12500 https://doi.org/10.1186/2051-5960-1-56 |
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Arctic |
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Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
http://resolver.sub.uni-goettingen.de/purl?gs-1/12500 Acta Neuropathologica Communications. 2013 Sep 06;1(1):56 doi:10.1186/2051-5960-1-56 24252153 |
op_rights |
openAccess http://creativecommons.org/licenses/by/2.0/ Antonios et al.; licensee BioMed Central Ltd. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1186/2051-5960-1-56 |
container_title |
Acta Neuropathologica Communications |
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1 |
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1 |
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56 |
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1766347823170715648 |