Gender- and age-dependent γ-secretase activity in mouse brain and its implication in sporadic Alzheimer disease Journal Article
| Authors: | Placanica, L.; Zhu, L.; Li, Y. M. |
| Article Title: | Gender- and age-dependent γ-secretase activity in mouse brain and its implication in sporadic Alzheimer disease |
| Abstract: | Alzheimer disease (AD) is an age-related disorder. Aging and female gender are two important risk factors associated with sporadic AD. However, the mechanism by which aging and gender contribute to the pathogenesis of sporadic AD is unclear. It is well known that genetic mutations in γ-secretase result in rare forms of early onset AD due to the aberrant production of Aβ42 peptides, which are the major constituents of senile plaques. However, the effect of age and gender on γ-secretase has not been fully investigated. Here, using normal wild-type mice, we show mouse brain γ-secretase exhibits gender- and age-dependent activity. Both male and female mice exhibit increased Aβ42:Aβ40 ratios in aged brain, which mimics the effect of familial mutations of Presenilin-1, Presenlin-2, and the amyloid precursor protein on Aβ production. Additionally, female mice exhibit much higher γ-secretase activity in aged brain compared to male mice. Furthermore, both male and female mice exhibit a steady decline in Notch1 γ-secretase activity with aging. Using a small molecule affinity probe we demonstrate that male mice have less active c-secretase complexes than female mice, which may account for the gender-associated differences in activity in aged brain. These findings demonstrate that aging can affect γ-secretase activity and specificity, suggesting a role for γ-secretase in sporadic AD. Furthermore, the increased APP γ-secretase activity seen in aged females may contribute to the increased incidence of sporadic AD in women and the aggressive Aβ plaque pathology seen in female mouse models of AD. In addition, deceased Notch γ-secretase activity may also contribute to neurodegeneration. Therefore, this study implicates altered γ-secretase activity and specificity as a possible mechanism of sporadic AD during aging. © 2009 Placanica et al. |
| Keywords: | controlled study; gene mutation; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; mus; disease association; animal experiment; animal model; age factors; enzymology; enzyme activity; mice, inbred c57bl; age; c57bl mouse; blotting, western; brain; protein synthesis; western blotting; aging; sex difference; enzyme specificity; catalytic domain; alzheimer disease; amyloid precursor protein; notch1 receptor; amyloid precursor protein secretases; secretase; gamma secretase; presenilin 1; presenilin 2; amyloid beta protein[1-40]; amyloid beta protein[1-42]; brain level; enzyme active site; photoaffinity labeling; photoaffinity labels |
| Journal Title: | PLoS ONE |
| Volume: | 4 |
| Issue: | 4 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2009-01-01 |
| Start Page: | e5088 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0005088 |
| PUBMED: | 19352431 |
| PROVIDER: | scopus |
| PMCID: | PMC2661375 |
| DOI/URL: | |
| Notes: | --- - Article No. e5088 - "Cited By (since 1996): 16" - "Export Date: 13 March 2012" - "Source: Scopus" |
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