Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer's disease pathogenesis?
Low density lipoprotein receptor-related protein (LRP) polymorphisms have recently been associated with an increased susceptibility of Alzheimer's disease (AD). Furthermore, LRP has been linked to molecules that confer susceptibility to AD (apolipoprotein E, alpha-2-macroglobulin, amyloid precursor protein), previously with the exception of the presenilins. Here we report that aberrant presenilin-1 expression in vivo and in vitro downregulates LRP. Specifically, transgenic mice overexpressing the M146L or L286V presenilin-1 mutation show decreased levels of LRP expression in neuronal populations where presenilin-1 and LRP are closely colocalized or coexpressed. Moreover, cell lines transfected with presenilin-1 also expressed decreased levels of LRP. These findings suggest that LRP may be central to AD pathogenesis since all proteins genetically associated with AD can now be linked via a single pathway to LRP.
Van Uden
E
E
School of Medicine, University of California at San Diego, La Jolla, California, 92093-0624, USA.
Carlson
G
G
St George-Hyslop
P
P
Westaway
D
D
Orlando
R
R
Mallory
M
M
Rockenstein
E
E
Masliah
E
E
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D053764:Presenilin-1; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics*; D011973:Receptors, LDL / Q000378:metabolism; D013004:Somatostatin / Q000032:analysis; D014158:Transcription, Genetic
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D013004:Somatostatin