Identification of amino-terminally and phosphotyrosine-modified carboxy-terminal fragments of the amyloid precursor protein in Alzheimer's disease and Down's syndrome brain

The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP ) are considered beta -amyloid (A beta) precursors as well as molecular spe cies that are both amyloidogenic and neurotoxic by themselves in vitro or i n animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study , we analylzed OTFs extracted from brains of subjects with AD, non-AD contr ol, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, sug gesting that the enhanced CTFs formation is important for the early occurre nce of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. Iii) CTFs modifi ed at their N-terminus appear to be the direct precursors of likewise N-ter minally modified A beta peptides, which constitute the most abundant specie s in AD and DS plaques. This observation suggests that N-truncated A beta p eptides are rather formed directly at beta -secretase level and not through a progressive proteolysis of full-length A beta1-40/42. (iii) Among the di fferently cleaved CTFs, only the 22- and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, sugge sting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a mole cular species directly involved in AD pathogenesis and in the development o f the AD-like pathology in DS subjects. (C) 2001 Academic Press.