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Papers In Press, published online ahead of print August 28, 2001
Dept. of Psychiatry, Molecular Neurobiology, University of Goettingen, Goettingen D-37073
Corresponding Author: jwiltfa{at}gwdg.de
One and two-dimensional urea-based A
J. Biol. Chem, 10.1074/jbc.M102790200
Submitted on March 29, 2001
Revised on August 9, 2001
Accepted on August 28, 2001
Elevation of Abeta peptide 2-42 in sporadic and familial Alzheimer's disease and its generation in PS1 knockout cells
-SDS-PAGE/immunoblots were used to analyse the generation of aminoterminal- and carboxyterminal-truncated beta-amyloid peptides (Nt- and Ct-truncated A peptides) in conditioned medium from primary mouse neurons and a neuroglioma cell line, as well as in human cerebrospinal fluid (CSF). A comparable and highly conserved pattern of A peptides, namely 1-40/42 and Ct-truncated 1-37, 1-38, 1-39 was found. Besides A1-42, we also observed a consistent elevation of the Nt-truncated A2-42 in a detergent-soluble pool in brains of subjects with Alzheimer´s disease (AD). A2-42 was also specifically elevated in CSF samples of AD patients. To decipher the contribution of potential different
-secretases (presenilins) for generating the Nt- and Ct-truncated A peptides, we overexpressed APP trafficking mutants in PS1+/+ and PS1-/- neurons. As compared to APP-WT, PS1-/- neurons and PS1+/+ neurons overexpressing APP-
ct (slow-internalizing mutant) show a decrease of all secreted A peptide species as expected since this mutant is mainly processed by
-secretase. This drop is even more pronounced for the APP-KK construct (ER retention motif). Surprisingly, A2-42 is significantly less affected in PS1-/- neurons and in neurons transfected with the endocytosis-deficient APP-ct construct. Our data confirm that PS1 is closely involved in the production of A1-40/42 and the Ct-truncated A1-37/38/39, but the Nt-truncated and Ct-elongated A2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter A peptide species could be generated by a Asp/Ala-secretase activivity.
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