Abstract

Synaptic degeneration is the first pathological hallmark in Alzheimer's disease and the one that correlates best with disease progression. The mechanism for synaptic degeneration is unknown but a strong candidate as a causative agent is amyloid β-peptide (Aβ) oligomers that may cause Ca2+ dysregulation and oxidative stress. Aβ is produced by the processing of the amyloid precursor protein (APP) by two sequential proteolytic events. The last cleavage is performed by a large membrane-bound protein complex called γ-secretase consisting of at least for components. In addition to APP, γ-secretase cleaves a large number of substrates which complicates its potential use as a theurapeutical target. In order to design specific γ-secretase inhibitors/ regulators it is important to increase the knowledge about this enzyme. Several studies have determined the subcellular localisation of γ-secretase to the late secretory-endosomal pathways using different cell-lines. However, the localization in brain has not been reported. Since the synapses seem to be particularly vulnerable for Aβ toxicity we wanted to examine if γ-secretase is localized to the synapses. Methods: We prepared synaptic membranes and synaptic vesicles using sucrose gradients and synaptosomal lysis, and assayed these fractions for subcellular markers, γ-secretase components and γ-secretase activity as measured by AICD and Aβ production. Results: The synaptic membrane fraction was enriched in PSD-95, a post-synaptic membrane marker, but also contained endosomal markers. The γ-secretase activity was dramatically enriched in this fraction, as assayed by endogenous AICD and Aβ production. It is possible that the γ-secretase in synaptic membranes could be differently regulated compared to other parts of the brain and we speculate that synaptic membrane preparations could be useful for finding γ-secretase inhibitors/ regulators that specifically interacts with the synaptic Aβ production. Conclusions: Gamma-secretase activity is enriched in synaptic membranes and high local production of Aβ might contribute to the synaptic degeneration seen in Alzheimer's disease

Keywords

Alzheimer´s disease; γ-secretase; Aβ; synaptic membranes

Published in

Alzheimer's and Dementia
2008, Volume: 4, number: 4, pages: T730

Conference

Alzheimer's Association International Conference on Alzheimer's Disease

SLU Authors

• Nahalkova, Jarmila

  • Department of Plant Biology, Swedish University of Agricultural Sciences
    

Permanent link to this page (URI)

https://res.slu.se/id/publ/22022