Amino-terminal modification and tyrosine phosphorylation of [corrected] 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 (Abeta) precursors as well as molecular species possibly amyloidogenic and neurotoxic by [corrected] in vitro or in animal models. The CTF's role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed brain extracted CTFs in subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS subjects CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaques deposition in DS. No significant difference in CTFs level [corrected] between AD and age-matched control cases. (ii) CTFs modified at their N-terminus are the direct precursors of similarly N-terminally modified Abeta peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated Abeta peptides are formed directly at beta-secretase level and not through a progressive proteolysis of full-length Abeta1-40/42. (iii) Among the differently cleaved CTFs, only the 22- and 12.5-kDa CTF polypeptides are tyrosine phosphorylated in both AD and control brain while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that APP and CTFs may be involved in different pathways depending on their length and sequences. This study provides evidence that CTFs constitute in human brain a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.
Russo
C
C
Section of Pharmacology and Neuroscience, National Cancer Institute, Genova, Italy.
Salis
S
S
Dolcini
V
V
Venezia
V
V
Song
X H
XH
Teller
J K
JK
Schettini
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D003720:Densitometry; D004314:Down Syndrome / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D019000:Phosphotyrosine / Q000737:chemistry*; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D010446:Peptide Fragments; D019000:Phosphotyrosine; D014443:Tyrosine; D011761:Pyrrolidonecarboxylic Acid