title: 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.affiliation: Georg-August-University Goettingen, University Medicine Goettingen, Division of Molecular Psychiatry, 37075 Goettingen, Germany. tbayer@gwdg.de.
authors.forename: Gregory
authors.initials: G
authors.lastname: Antonios
authors.forename: Nasrin
authors.initials: N
authors.lastname: Saiepour
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bouter
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Richard
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Auli
authors.initials: A
authors.lastname: Verkkoniemi-Ahola
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018604:Epitope Mapping; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000503:physiopathology; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D018696:Neuroprotective Agents