Abstract
Amyloidogenic processing of APP by β- and γ-secretases leads to the generation of amyloid-β peptide (Aβ), and the accumulation of Aβ in senile plaques is a hallmark of Alzheimer’s disease (AD). Understanding the mechanisms of APP processing is therefore paramount. Increasing evidence suggests that APP intracellular domain (AICD) interacting proteins influence APP processing. In this study, we characterized the overexpression of AICD interactor GULP1 in a Drosophila AD model expressing human BACE and APP695. Transgenic GULP1 significantly lowered the levels of both Aβ1-40 and Aβ1-42 without decreasing the BACE and APP695 levels. Overexpression of GULP1 also reduced APP/BACE-mediated retinal degeneration, rescued motor dysfunction and extended longevity of the flies. Our results indicate that GULP1 regulate APP processing and reduce neurotoxicity in a Drosophila AD model.
Highlights
Human GULP1, the homologue of Caenorhabditis elegans CED-6, is an adaptor protein with multiple protein interaction domains/regions including an N-terminal phosphotyrosine-binding (PTB) domain, a centrally located leucine zipper and a carboxyl terminal proline/ serine rich region [1,2,3]
To investigate the hypothesis that GULP1 reduces degeneration in the Drosophila Alzheimer’s disease (AD) model, we examined the ommatidial organization of gmr > GULP1, amyloid precursor protein (APP), BACE fly by pseudopupil assay
The current study provides first evidence that GULP1 affects human APP metabolism in vivo and improve structural, behavioral and longevity phenotypes in a Drosophila AD model
Summary
Human GULP1 (engulfment adaptor PTB-domaincontaining 1), the homologue of Caenorhabditis elegans CED-6, is an adaptor protein with multiple protein interaction domains/regions including an N-terminal phosphotyrosine-binding (PTB) domain, a centrally located leucine zipper and a carboxyl terminal proline/ serine rich region [1,2,3]. GULP1/CED-6 has been implicated in phagocytosis as it interacts with several engulfment receptors including CED-1, stabilin-1 and stabilin-2 [3,4,5,6]. We and others have shown that GULP1 PTB domain binds to Alzheimer’s disease amyloid precursor protein (APP) [7, 8]. Amyloidogenic processing of APP by β- and γ-secretases leads to the generation of amyloid-β peptide (Aβ), and accumulation of Aβ to form senile plaques is a hallmark of Alzheimer’s disease (AD). The mechanisms by which APP processing is regulated are still not fully understood, increasing evidence suggests that AICD interacting proteins can influence APP metabolism and Aβ generation (see reviews [9, 10]). The effect of GULP1 on Aβ production in vivo remains to be determined
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