Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce ß-amyloid in Alzheimer's disease.
β-Amyloid (Aβ) accumulation in the brain is widely accepted to be critical to the development of Alzheimer's disease (AD). Current efforts at reducing toxic Aβ40 or 42 have largely focused on modulating γ-secretase activity to produce shorter, less toxic Aβ, while attempting to spare other secretase functions. In this paper we provide data that offer the potential for a new approach for the treatment of AD. The method is based on our previous findings that the production of Aβ from the interaction between the β-amyloid precursor protein (APP) and Presenilin (PS), as part of the γ-secretase complex, in cell culture is largely inhibited if the entire water-soluble NH2-terminal domain of PS is first added to the culture. Here we demonstrate that two small, non-overlapping water-soluble peptides from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Aβ as well as Aβ40 and 42 in vitro and in vivo in the brains of APP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Aβ production is largely focused in a few smaller sequences within that domain. Using biolayer interferometry and confocal microscopy we provide evidence that peptides effective in reducing Aβ give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. Finally, we demonstrate that the reduction of Aβ by the peptides does not affect the catalytic activities of β- or γ-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Aβ production in model systems of AD. These peptides and their derivatives offer new potential drug candidates for the treatment of AD.
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, United States of America; Cenna Biosciences Incorporated, 505 Coast Boulevard, Suite 302, La Jolla, CA, 92037, United States of America.
Nazneen N
NN
Dewji
Department of Biology, University of California San Diego, La Jolla, CA, 92093, United States of America; Cenna Biosciences Incorporated, 505 Coast Boulevard, Suite 302, La Jolla, CA, 92037, United States of America.
S Jonathan
SJ
Singer
Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, United States of America; Department of Pathology, University of California San Diego, La Jolla, CA, 92093, United States of America.
Eliezer
E
Masliah
Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, United States of America.
Edward
E
Rockenstein
Department of Medicine, University of California San Diego, La Jolla, CA, 92093, United States of America; Cenna Biosciences Incorporated, 505 Coast Boulevard, Suite 302, La Jolla, CA, 92037, United States of America.
Mihyun
M
Kim
FortéBio, Pall Corporation, 1360 Willow Rd, Suite 201, Menlo Park, CA, 94025, United States of America.
Martha
M
Harber
Department of Neuroscience Imaging Core, University of California San Diego, La Jolla, CA, 92093, United States of America.
Taylor
T
Horwood
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000737:chemistry* / Q000627:therapeutic use*
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1