Respective contribution of Appl to mushroom body axon growth and long-term memory inDrosophila

Abstract

SummaryThe Amyloid Precursor Protein (APP) is linked to Alzheimer’s disease.Applis the singleDrosophilaAPP ortholog and is expressed in all neurons throughout development. Appl was previously shown to modulate, cell-autonomously, axon outgrowth in the mushroom bodies (MBs), the fly olfactory memory center. Furthermore,Applknockdown in the MBs results in loss of memory following the association of odorants with electric shocks. Nevertheless, the memory defects of flies devoid of Appl remains unknown becauseAppldflies, carrying the only known null allele, show an abnormal response to electric shock. We found thatAppldaffects the normal function ofvnd, the gene just proximal toAppl. We report here thatvndis required for MB β-branch axon outgrowth. Moreover,vndis expressed in neurons close to, but not within, the MB during development and is required non-cell-autonomously for MB axon outgrowth. To decipher developmental and memory defects specifically due to a loss of onlyApplfunction, we generated a preciseApplnull allele (ApplC2.1) by CRISPR/Cas9 genomic engineering. WithApplC2.1, we confirmed the partial requirement forApplin MB axon outgrowth but found no defects of electric shock avoidance, allowing us to test for potential memory defects.ApplC2.1flies showed a complete loss of long-term memory which was fully rescued by MB-restricted expression ofAppl+only during the adult stage. Therefore, we demonstrate that the complete lack of Appl affects memory independently from structural developmental defects.