Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment

Franziska Rieche, Katia Carmine-Simmen, Burkhard Poeck, Doris Kretzschmar, Roland Strauss

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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. Walking flies can memorize the path to a vanished landmark for about 4 s by integrating visual and idiothetic information about their own movements. Rieche et al. show that this memory is rapidly deteriorating with age and depends on amyloid precursor protein-like (APPL) signaling. Reducing cleavage of APPL ameliorates age-related memory deficits.

Original languageEnglish (US)
Pages (from-to)817-823.e3
JournalCurrent Biology
Volume28
Issue number5
DOIs
StatePublished - Mar 5 2018

Keywords

  • Amyloid Precursor Protein
  • Drosophila
  • Fasciclin 2
  • age-related memory impairment
  • central complex
  • visual orientation
  • working memory

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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