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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


Year of Publication:
Contact PI Name:
Nazneen N. Dewji
Contact PI Affiliation:
Department of Medicine, University of California San Diego, La Jolla, California, USA
S. Jonathan Singer, Eliezer Masliah, Edward Rockenstein, Mihyun Kim, Martha Harber, Taylor Horwood
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer's Drug Discovery Foundation (ADDF)
Study Goal and Principal Findings:

This report provides data that offers the potential for a new and effective approach for the treatment of AD, based on an Aβ-lowering strategy that does not involve the inhibition of the APP secretases.  Previous work from this lab demonstrated that the specific binding of APP with PS is a required initial step in the production of Aβ.In that work a specific NH2-terminal domain (residues 1–80) of PS was used to inhibit PS-APP interaction; was found to markedly inhibit Aβ production.  This report builds upon these findings and aims at testing several isolated, small soluble peptides, from within the NH2-terminal domain of PS-1, for efficacy in inhibiting Aβ production. Data indicate that two small, non-overlapping water-soluble peptides ( P4 and P8) 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 mThy1-hAPP 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. The peptides that were most effective in reducing total Aβ and of Aβ 40 and 42 exhibited strong and specific binding with the ectodomain of APP 695. 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.  The author posits that these peptides and their derivatives offer new potential drug candidates for the treatment of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
PS-1 N-Terminal Peptides
Therapeutic Target:
gamma Secretase

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
C57BL/6 x DBA

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Binding Affinity Measurements
Amyloid Precursor Protein (APP) Metabolites
Notch Cleavage
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)