Reference Report

Reference
Citation	Wentzell, J.S., Bolkan, B.J., Carmine-Simmen, K., Swanson, T.L., Musashe, D.T., Kretzschmar, D. (2012). Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration. Neurobiol. Disease 46(1): 78--87. (Export to RIS)
FlyBase ID	FBrf0217742
Publication Type	Research paper
PubMed ID	22266106
PubMed Abstract	The processing of Amyloid Precursor Proteins (APPs) results in several fragments, including soluble N-terminal ectodomains (sAPPs) and C-terminal intracellular domains (AICD). sAPPs have been ascribed neurotrophic or neuroprotective functions in cell culture, although β-cleaved sAPPs can have deleterious effects and trigger neuronal cell death. Here we describe a neuroproprotective function of APP and fly APPL (Amyloid Precursor Protein-like) in vivo in several Drosophila mutants with progressive neurodegeneration. We show that expression of the N-terminal ectodomain is sufficient to suppress the progressive degeneration in these mutants and that the secretion of the ectodomain is required for this function. In addition, a protective effect is achieved by expressing kuzbanian (which has α-secretase activity) whereas expression of fly and human BACE aggravates the phenotypes, suggesting that the protective function is specifically mediated by the α-cleaved ectodomain. Furthermore, genetic and molecular studies suggest that the N-terminal fragments interact with full-length APPL activating a downstream signaling pathway via the AICD. Because we show protective effects in mutants that affect different genes (AMP-activated protein kinase, MAP1b, rasGAP), we propose that the protective effect is not due to a genetic interaction between APPL and these genes but a more general aspect of APP proteins. The result that APP proteins and specifically their soluble α-cleaved ectodomains can protect against progressive neurodegeneration in vivo provides support for the hypothesis that a disruption of the physiological function of APP could play a role in the pathogenesis of Alzheimer's Disease.
DOI	10.1016/j.nbd.2011.12.047
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Neurobiol. Disease
Title	Neurobiology of Disease
Publication Year	1994-
ISBN/ISSN	0969-9961
Data from Reference
Alleles (17)
	Appl^d Appl^{dAICD.Scer\UAS.T:Ivir\HA1} Appl^{s.Scer\UAS.T:Ivir\HA1} Appl^{Scer\UAS.cCSa} Appl^sd.Scer\UAS Bace^{Scer\UAS.cCSa} futsch^olk1 Hsap\APP^{695.Scer\UAS.Exel} Hsap\APP^{s.α.Scer\UAS.T:Ivir\HA1} Hsap\APP^{s.β.Scer\UAS.T:Ivir\HA1} Hsap\BACE1^Scer\UAS.cGa kuz^Scer\UAS.cFa Scer\GAL4^Appl.G1a Scer\GAL4^elav-C155 SNF4Aγ^loe sws¹ vap^KS67
Constructs (11)
	P{Appl-GAL4.G1a} P{UAS-APP.695.Exel} P{UAS-APP.s.α.HA} P{UAS-APP.s.β.HA1} P{UAS-Appl.CS} P{UAS-Appl.dAICD.HA} P{UAS-Appl.s.HA} P{UAS-Appl.sd} P{UAS-BACE1.G} P{UAS-Bace.CS} P{UAS-kuz.F}
Genes (11)
	Appl Bace futsch Hsap\APP Hsap\BACE1 kuz Scer\GAL4 SNF4Aγ sws T:Ivir\HA1 vap
Insertions (2)
	P{GawB}elav^C155 P{lacW}SNF4Aγ^loe
Natural transposons (1)
	P-element