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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

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          Abstract

          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 NH 2-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 NH 2-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.

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          High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.

          Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Abeta peptides. The platelet-derived growth factor beta chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Abeta(1-42) levels, whereas an experimental mutation of the beta-secretase cleavage site (671(M-->I)) eliminated production of human Abeta. High levels of Abeta(1-42) resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Abeta levels but not with hAPP levels or plaque load. We conclude that Abeta is synaptotoxic even in the absence of plaques and that high levels of Abeta(1-42) are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions.
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            Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo.

            Aggregation of amyloid-beta (Abeta) peptide into soluble and insoluble forms within the brain extracellular space is central to the pathogenesis of Alzheimer's disease. Full-length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce Abeta. Abeta is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Abeta generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Abeta levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF Abeta levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Abeta. We estimate that approximately 70% of ISF Abeta arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity. These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention.
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              Notch signaling: from the outside in.

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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 April 2015
                2015
                : 10
                : 4
                : e0122451
                Affiliations
                [1 ]Department of Medicine, University of California San Diego, La Jolla, CA, 92093, United States of America
                [2 ]Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, United States of America
                [3 ]Department of Pathology, University of California San Diego, La Jolla, CA, 92093, United States of America
                [4 ]Department of Biology, University of California San Diego, La Jolla, CA, 92093, United States of America
                [5 ]Cenna Biosciences Incorporated, 505 Coast Boulevard, Suite 302, La Jolla, CA, 92037, United States of America
                [6 ]FortéBio, Pall Corporation, 1360 Willow Rd, Suite 201, Menlo Park, CA, 94025, United States of America
                [7 ]Department of Neuroscience Imaging Core, University of California San Diego, La Jolla, CA, 92093, United States of America
                Massachusetts General Hospital, UNITED STATES
                Author notes

                Competing Interests: NND and SJS have ownership of stocks in Cenna Biosciences Inc and are authors on patent applications filed by UCSD. One of the authors, Dr. Martha Harber, is employed by a commercial company “FortéBio, Pall Corporation”. Neither Dr. Harber nor ForteBio are employed by Cenna, are consultants for Cenna, or stand to gain financially or otherwise from this work. They are not a part of the patents or products that may be developed from this work, or part of any grants or gifts. Dr. Harber and ForteBio have no non-financial competing interests, including professional or personal. The authors have patents relating to material pertinent to this article. The details of the patents, including name and number, are as follows: Methods and compositions for treating neurodegenerative disorders and Alzheimer's disease and improving normal memory. Dewji, NN and Singer, SJ, United States Patent No. 8,129,334, Mar. 6, 2012. Methods and compositions for treating neurodegenerative disorders and Alzheimer’s disease and improving normal memory. Dewji, NN and Singer, SJ, United States Patent No. 8399478, Mar. 5, 2013.

                Conceived and designed the experiments: NND EM SJS MH. Performed the experiments: NND EM ER MK MH TH. Analyzed the data: NND EM ER MK MH TH. Contributed reagents/materials/analysis tools: MH TH. Wrote the paper: NND EM SJS MH.

                Article
                PONE-D-14-33918
                10.1371/journal.pone.0122451
                4414571
                25923432
                f3ed3acb-884f-41c6-86e1-1fb5165f2937
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 29 July 2014
                : 12 February 2015
                Page count
                Figures: 8, Tables: 3, Pages: 22
                Funding
                Supported by National Institutes of Health grants 5RO1NS055161, 5RO1AG17888, 1R43AG043278 and Alzheimer’s Drug Discovery Foundation to NND, and National Institutes of Health grants AG18440, AG022074, AG011385, AG03197, NS057096 to EM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                All relevant data are within the paper.

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