Carboxyl-terminal fragments of presenilin-1 are closely related to cytoskeletal abnormalities in Alzheimer's brains

To clarify the role of presenilin-1 (PS-1) in the pathology of Alzheimer's disease (AD), we tested four antisera to PS-1. The specific antisera to the N-terminus (HSN-2) and C-terminus (HS-C) of PS-1 detected a 44/40kD holo-p rotein, a 25kD N-terminal fragment (NTF) and a 16kD C-terminal fragment (CT F) of PS-1 in COS-7 cells. The 25kD NTF and 16kD CTF were observed in human brains, and their amounts were not significantly different between the con trol and AD brains. The antibody HS-C labeled extensive neurofibrillary tan gles, dystrophic neurites and curly fibers in the AD brains, In the paired helical filament (PHF) fraction containing A68 protein-from AD brains, a sm ear pattern of CTFs was revealed. Antisera (HS-L292 and HS-L300) to cleavag e sites of PS-1 also revealed immunoreactive neurofibrillary tangles in the AD brain sections and the: smear pattern of CTFs of A68 protein fraction. The CTFs of PS-1 accumulate with PHF tau, suggesting a close relationship b etween PS-1 and cytoskeletal abnormalities in AD brains. (C) 1999 Academic Press.