NIF LinkOut Portal

Options
Only Pubmed Central
Include Pubmed Central
Sections
Title
Abstract
Introduction
Methods
Results
Supplement
Appendix
Contributions
Background
Commentary
Funding
Limitations
Caption
FILTERS

Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.

Authors:
Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li YM, Zheng H
Affiliation:
Journal:
The Journal of neuroscience : the official journal of the Society for Neuroscience

Abstract

gamma-Secretase processing of the amyloid precursor protein (APP) generates Abeta40 and Abeta42, peptides that constitute the principal components of the beta-amyloid plaque pathology of Alzheimer's disease (AD). The gamma-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced gamma-secretase cleavage at the Abeta40, but not the Abeta42, site. Surprisingly, this reduction of Abeta40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in gamma-secretase processing, and decreased Abeta40, not increased Abeta42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Abeta40 against amyloid pathology and raises the possibility that impaired gamma-secretase activity could be the basis for AD pathogenesis in general.

  1. Welcome

    Welcome to NIF. Explore available research resources: data, tools and materials, from across the web

  2. Community Resources

    Search for resources specially selected for NIF community

  3. More Resources

    Search across hundreds of additional biomedical databases

  4. Literature

    Search Pub Med abstracts and full text from PubMed Central

  5. Insert your Query

    Enter your search terms here and hit return. Search results for the selected tab will be returned.

  6. Join the Community

    Click here to login or register and join this community.

  7. Categories

    Narrow your search by selecting a category. For additional help in searching, view our tutorials.

  8. Query Info

    Displays the total number of search results. Provides additional information on search terms, e.g., automated query expansions, and any included categories or facets. Expansions, filters and facets can be removed by clicking on the X. Clicking on the + restores them.

  9. Search Results

    Displays individual records and a brief description. Click on the icons below each record to explore additional display options.

X