The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPα fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPα in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products.
Pubmed ID: 29478851 RIS Download
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View all literature mentionsCollects, maintains and distributes Drosophila melanogaster strains for research. Emphasis is placed on genetic tools that are useful to a broad range of investigations. These include basic stocks of flies used in genetic analysis such as marker, balancer, mapping, and transposon-tagging strains; mutant alleles of identified genes, including a large set of transposable element insertion alleles; defined sets of deficiencies and a variety of other chromosomal aberrations; engineered lines for somatic and germline clonal analysis; GAL4 and UAS lines for targeted gene expression; enhancer trap and lacZ-reporter strains with defined expression patterns for marking tissues; and a collection of transposon-induced lethal mutations.
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View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis polyclonal targets Appl
View all literature mentionsThis unknown targets Mouse IgG (H+L)
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View all literature mentionsThis unknown targets RFP
View all literature mentionsThis polyclonal targets Green Fluorescent Protein (GFP)
View all literature mentionsThis monoclonal targets RFP Antibody
View all literature mentionsThis polyclonal targets Green Fluorescent Protein (GFP)
View all literature mentionsThis monoclonal targets Mouse Drosophila fasciclin II
View all literature mentionsDrosophila melanogaster with name w[1118]; P{GD14486}v36350 from Flybase.
View all literature mentionsDrosophila melanogaster with name y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF02878}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name Appl[d] w[*] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+mC]=UAS-kuz.F}DF1 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[1118]; P{w[+mC]=UAS-APP.695.Exel}5 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=UAS-Appl.sdDeltaE2}3 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=UAS-Appl.sdDeltaE1}3 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[*]; P{w[+mC]=UAS-Appl.s}2 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=UAS-Appl.sd}2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[*]; P{w[+mC]=UAS-CD4-tdGFP}8M2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[*] P{w[+mC]=UAS-mCD8::GFP.L}Ptp4E[LL4]; betaTub60D[Pin-Yt]/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+mC]=tubP-GAL80[ts]}20; TM2/TM6B, Tb[1] from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[*]; betaTub60D[Pin-1]/CyO; P{w[+mW.hs]=GawB}EB1 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+m*]=GAL4-ftz.ng}3/TM3, P{w[+mC]=act-lacZ.B}JT1, Sb[1] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+mW.hs]=GawB}lilli[189Y] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*] P{w[+mW.hs]=GawB}c105[c105] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; Psn[143]/TM6B, Tb[1] from BDSC.
View all literature mentionsDrosophila melanogaster with name kuz[e29-4]/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name Canton-S from BDSC.
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