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 ? peptide (A?) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated A? peptides especially N-truncated pyroglutamate A?pE3-42 have been extensively studied. Together with full-length A?1-42 and A?1-40, N-truncated A?pE3-42 and A?4-42 are major variants in AD brain. Although A?4-42 has been known for a much longer time, there is a lack of studies addressing the question whether A?pE3-42 or A?4-42 may precede the other in Alzheimer's disease pathology.

Results

Using different A? antibodies specific for the different N-termini of N-truncated A?, we discovered that A?4-x preceded A?pE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel A?4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated A? species. While NT4X-167 significantly rescued A?4-42 toxicity in vitro no beneficial effect was observed against A?1-42 or A?pE3-42 toxicity. Phenylalanine at position four of A? 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 PS1?9 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

A?4-x precedes A?pE3-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 A?4-x and represents a novel tool in Alzheimer research.

SUBMITTER: Antonios G 

PROVIDER: S-EPMC3893517 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature