title: The full-length form of the Drosophila amyloid precursor protein is involved in memory formation.
abstract: The APP plays a central role in AD, a pathology that first manifests as a memory decline. Understanding the role of APP in normal cognition is fundamental in understanding the progression of AD, and mammalian studies have pointed to a role of secreted APPα in memory. In Drosophila, we recently showed that APPL, the fly APP ortholog, is required for associative memory. In the present study, we aimed to characterize which form of APPL is involved in this process. We show that expression of a secreted-APPL form in the mushroom bodies, the center for olfactory memory, is able to rescue the memory deficit caused by APPL partial loss of function. We next assessed the impact on memory of the Drosophila α-secretase kuzbanian (KUZ), the enzyme initiating the nonamyloidogenic pathway that produces secreted APPLα. Strikingly, KUZ overexpression not only failed to rescue the memory deficit caused by APPL loss of function, it exacerbated this deficit. We further show that in addition to an increase in secreted-APPL forms, KUZ overexpression caused a decrease of membrane-bound full-length species that could explain the memory deficit. Indeed, we observed that transient expression of a constitutive membrane-bound mutant APPL form is sufficient to rescue the memory deficit caused by APPL reduction, revealing for the first time a role of full-length APPL in memory formation. Our data demonstrate that, in addition to secreted APPL, the noncleaved form is involved in memory, raising the possibility that secreted and full-length APPL act together in memory processes.
authors.affiliation: Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI-ParisTech, PSL Research University, 75005 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdet
authors.affiliation: Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI-ParisTech, PSL Research University, 75005 Paris, France valerie.goguel@espci.fr thomas.preat@espci.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Preat
authors.affiliation: Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI-ParisTech, PSL Research University, 75005 Paris, France valerie.goguel@espci.fr thomas.preat@espci.fr.
authors.forename: Valérie
authors.identifier: http://orcid.org/0000-0002-6602-1969
authors.initials: V
authors.lastname: Goguel
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology*; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D024521:Mushroom Bodies / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
chemical_list: C066839:Appl protein, Drosophila; D019483:Disintegrins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C100953:KUZ protein, Drosophila; D008666:Metalloendopeptidases
keywords: APPL; Drosophila; kuzbanian; mushroom bodies; short-term memory; α-secretase