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N-truncated Abeta s...
N-truncated Abeta starting with position four : early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody
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Antonios, Gregory (author)
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Saiepour, Nasrin (author)
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Bouter, Yvonne (author)
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Richard, Bernhard C (author)
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Paetau, Anders (author)
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Verkkoniemi-Ahola, Auli (author)
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik
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- Ingelsson, Martin (author)
- Uppsala universitet,Geriatrik
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Kovacs, Gabor G (author)
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Pillot, Thierry (author)
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Wirths, Oliver (author)
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Bayer, Thomas A (author)
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(creator_code:org_t)
- Springer Science and Business Media LLC, 2013
- 2013
- English.
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In: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1, s. 56-
- Related links:
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https://actaneurocom...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
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- art (subject category)
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Antonios, Gregor ...
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Saiepour, Nasrin
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Bouter, Yvonne
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Richard, Bernhar ...
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Paetau, Anders
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Verkkoniemi-Ahol ...
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show more...
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Lannfelt, Lars
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Ingelsson, Marti ...
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Kovacs, Gabor G
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Pillot, Thierry
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Wirths, Oliver
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Bayer, Thomas A
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Geriatrics
- Articles in the publication
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Acta neuropathol ...
- By the university
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Uppsala University