Commentary: Aβ N- Terminal Isoforms: Critical contributors in the course of AD pathophysiology

• Published in: Journal of Alzheimer's disease 2001-01, Vol.3 (2), p.241-248
• Main Author: Tekirian, Tina L.
• Format: Article
• Language: English
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-2001-3209

The assessment of protein or amino acid variations across evolution allows one to glean divergent features of disease-specific pathology. Within the Alzheimer's disease (AD) literature, extensive differences in Aβ processing across cell lines and evolution have clearly been observed. In the recent past, increased levels of amyloid β Aβ1-42 have been heralded to be what distinguishes whether one is prone to the development of AD [59]. However, observations in naturally occurring, non-transgenic animals which display a great deal of parenchymal Aβ1-42 (Aβ found within extracellular plaque deposits) and a complete lack of β1-40 within these same Aβ1-42 plaques raise the issue of whether Aβx-42 (Aβ that is truncated or modified at the N- terminus), rather than Aβ1-42, is instead the critical mediator of Aβ production and pathogenesis [47,49]. Distinct ratios of Aβ N-terminal variants (i.e. Aβ1-x, Aβ3-x, Aβ11-x, β17-x) have been assessed in human amyloid plaques [18,21,40,41,42,47,48,49,52]. Moreover, ratios of specific Aβ N-terminal variants separate naturally occurring, non-transgenic animals which develop abundant levels of Aβx-42 and not Aβx-40 from human AD participants who harbor plaques that contain both the Aβx-42 and Aβx-40 variants [49]. Next, Teller and colleagues have demonstrated the presence of N-terminal truncated soluble 3kD (likely Aβ17-x) and 3.7kD peptides (in addition to 4kD Aβ) well before the appearance of amyloid plaques in Down Syndrome brain [51], indicating an early contribution of the β N-terminus to the formation of amyloid pathology. Additional critical facts concerning the major contribution of the Aβ N-terminus in AD pathogenesis include observations which support thatβ generated by rodent neurons is predominantly truncated at Aβ11-x [13], the major form of APP C-terminal fragments in mice lacking functional PS1 is AβPP11-98 [9], β11-x expression is increased as a function of BACE expression [55], and an interrelationship between presenilin-1 mutations and increased levels of N-terminally truncatedβ [40]. This commentary highlights current understanding and potential biochemical, pathological, and cell biological contributions of Aβ N-terminal variants implicated during the course of AD pathogenesis. Although the amyloid β protein precursor (AβPP) gene and Aβ are highly conserved across mammalian species, there are species-specific differences. For instance, the primate, guinea pig, canine, and polar bear share an identical Aβ seq