Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice.
The activities of presenilin 1 (PS1) and 2 modulate the proteolytic processing of amyloid precursor proteins to produce Abeta1-42, and mutations in these proteins are associated with an accelerated rate of Abeta deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Abeta deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Abeta deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of beta-amyloid is not proportional to the level of transgene expression.
Borchelt
David R
DR
Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205, USA. drbor@jhmi.edu
Lee
Michael K
MK
Gonzales
Victoria
V
Slunt
Hilda H
HH
Ratovitski
Tamara
T
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Price
Donald L
DL
Sisodia
Sangram S
SS
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D010450:Endopeptidases / Q000737:chemistry; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1; D012333:RNA, Messenger / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D010450:Endopeptidases