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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 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.

Authors+Show Affiliations

Georg-August-University Goettingen, University Medicine Goettingen, Division of Molecular Psychiatry, 37075 Goettingen, Germany. tbayer@gwdg.de.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24252153

Citation

Antonios, Gregory, et al. "N-truncated Abeta Starting With Position Four: Early Intraneuronal Accumulation and Rescue of Toxicity Using NT4X-167, a Novel Monoclonal Antibody." Acta Neuropathologica Communications, vol. 1, 2013, p. 56.
Antonios G, Saiepour N, Bouter Y, et al. N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. Acta Neuropathol Commun. 2013;1:56.
Antonios, G., Saiepour, N., Bouter, Y., Richard, B. C., Paetau, A., Verkkoniemi-Ahola, A., ... Bayer, T. A. (2013). N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. Acta Neuropathologica Communications, 1, p. 56. doi:10.1186/2051-5960-1-56.
Antonios G, et al. N-truncated Abeta Starting With Position Four: Early Intraneuronal Accumulation and Rescue of Toxicity Using NT4X-167, a Novel Monoclonal Antibody. Acta Neuropathol Commun. 2013 Sep 6;1:56. PubMed PMID: 24252153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. AU - Antonios,Gregory, AU - Saiepour,Nasrin, AU - Bouter,Yvonne, AU - Richard,Bernhard C, AU - Paetau,Anders, AU - Verkkoniemi-Ahola,Auli, AU - Lannfelt,Lars, AU - Ingelsson,Martin, AU - Kovacs,Gabor G, AU - Pillot,Thierry, AU - Wirths,Oliver, AU - Bayer,Thomas A, Y1 - 2013/09/06/ PY - 2013/08/08/received PY - 2013/08/10/accepted PY - 2013/11/21/entrez PY - 2013/11/21/pubmed PY - 2013/11/21/medline SP - 56 EP - 56 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 1 N2 - 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. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/24252153/N_truncated_Abeta_starting_with_position_four:_early_intraneuronal_accumulation_and_rescue_of_toxicity_using_NT4X_167_a_novel_monoclonal_antibody_ L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-56 DB - PRIME DP - Unbound Medicine ER -