Deletion of presenilin 1 hydrophilic loop sequence leads to impaired γ-secretase activity and exacerbated amyloid pathology Journal Article
| Authors: | Deng, Y.; Tarassishin, L.; Kallhoff, V.; Peethumnongsin, E.; Wu, L.; Li, Y. M.; Zheng, H. |
| Article Title: | Deletion of presenilin 1 hydrophilic loop sequence leads to impaired γ-secretase activity and exacerbated amyloid pathology |
| Abstract: | γ-Secretase processing of the amyloid precursor protein (APP) generates Aβ 40 and Aβ 42, peptides that constitute the principal components of the β-amyloid plaque pathology of Alzheimer's disease (AD). The γ-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 γ-secretase cleavage at the Aβ 40, but not the Aβ 42, site. Surprisingly, this reduction of Aβ 40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in γ-secretase processing, and decreased Aβ 40, not increased Aβ 42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Aβ 40 against amyloid pathology and raises the possibility that impaired γ-secretase activity could be the basis for AD pathogenesis in general. Copyright © 2006 Society for Neuroscience. |
| Keywords: | controlled study; exon; pathogenesis; nonhuman; protein domain; protein function; mouse; animals; mice; mice, knockout; animal tissue; protein degradation; animal experiment; animal model; membrane proteins; enzyme activation; enzyme activity; structure-activity relationship; homozygosity; protein processing; amino acid sequence; molecular sequence data; brain; nucleotide sequence; mutagenesis, site-directed; protein structure, tertiary; disease exacerbation; alzheimer disease; amyloid precursor protein; amyloid precursor protein secretases; presenilin; gamma secretase; presenilin 1; presenilin-1; amyloid beta protein[1-40]; amyloid beta protein[1-42]; amyloid beta-protein; endopeptidases; hydrophilicity; alzheimer's disease; homodimer; γ-secretase; amyloid protein; aspartic endopeptidases; amyloid peptides; knock-in mice |
| Journal Title: | The Journal of Neuroscience |
| Volume: | 26 |
| Issue: | 14 |
| ISSN: | 0270-6474 |
| Publisher: | Society for Neuroscience |
| Date Published: | 2006-04-05 |
| Start Page: | 3845 |
| End Page: | 3854 |
| Language: | English |
| DOI: | 10.1523/jneurosci.5384-05.2006 |
| PUBMED: | 16597739 |
| PROVIDER: | scopus |
| PMCID: | PMC6674120 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 47" - "Export Date: 4 June 2012" - "CODEN: JNRSD" - "Source: Scopus" |
