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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ftunivhelsihelda:oai:helda.helsinki.fi:10138/156276 2023-08-20T04:04:58+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 2015-08-22T04:04:38Z application/pdf http://hdl.handle.net/10138/156276 eng eng BioMed Central Acta Neuropathologica Communications. 2013 Sep 06;1(1):56 http://hdl.handle.net/10138/156276 Antonios et al.; licensee BioMed Central Ltd. http://purl.org/eprint/entityType/ScholarlyWork http://purl.org/eprint/entityType/Expression http://purl.org/eprint/type/JournalArticle 2015 ftunivhelsihelda 2023-07-28T06:05:46Z 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. Article in Journal/Newspaper Arctic Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto Arctic |
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Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
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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. |
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 |
publisher |
BioMed Central |
publishDate |
2015 |
url |
http://hdl.handle.net/10138/156276 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
Acta Neuropathologica Communications. 2013 Sep 06;1(1):56 http://hdl.handle.net/10138/156276 |
op_rights |
Antonios et al.; licensee BioMed Central Ltd. |
_version_ |
1774715387459403776 |