N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibodyReportar como inadecuado




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Acta Neuropathologica Communications

, 1:56

First Online: 06 September 2013Received: 08 August 2013Accepted: 10 August 2013

Abstract

BackgroundThe 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.

ResultsUsing 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.

ConclusionsAβ4-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.

KeywordsPyroglutamate Abeta Abeta oligomer Toxicity Arctic Swedish Presenilin-1 5XFAD Transgenic mouse model Familial Alzheimer’s disease Sporadic Alzheimer’s disease Abeta 4-40 Abeta 4–42 Electronic supplementary materialThe online version of this article doi:10.1186-2051-5960-1-56 contains supplementary material, which is available to authorized users.

Gregory Antonios, Nasrin Saiepour, Yvonne Bouter, Bernhard C Richard contributed equally to this work.

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Autor: Gregory Antonios - Nasrin Saiepour - Yvonne Bouter - Bernhard C Richard - Anders Paetau - Auli Verkkoniemi-Ahola - Lars La

Fuente: https://link.springer.com/



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