Pasquer, L. | bioRxiv Science

bioRxiv2023

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

The Amyloid Precursor Protein (APP) is associated with Alzheimers disease. Appl is the single Drosophila APP ortholog and is expressed in all neurons throughout development. Appl was previously shown to cell-autonomously modulate axon outgrowth in the mushroom bodies (MBs), the fly olfactory memory center. However, we found that Appld, the only reported null allele, affects the normal function of vnd, the gene just proximal to Appl. To decipher developmental defects specifically due to a loss of only Appl function, we generated a precise Appl null allele (ApplC2.1) by CRISPR/Cas9 genomic engineering. With ApplC2.1, we confirmed the partial requirement for Appl in MB axon outgrowth. We also produced new CRISPR vnd alleles removing either vnd-B or vnd-A function. We report here that vnd is also required for MB {beta}-branch axon outgrowth and to a much greater extent than Appl itself. Moreover, vnd is expressed in neurons close to, but not within, the MB during development and is required non-cell-autonomously for MB axon outgrowth

neuroscience↗

bioRxiv2023

Long-term memory formation depends on an astrocyte-to-neuron H2O2 signaling

Astrocytes interact with neurons during cognitive processes1. In particular, astrocytes help neurons to fight oxidative stress2, a needed function since active neurons are prone to reactive oxygen species (ROS) damage due to their high mitochondrial activity and relatively poor antioxidant defenses3. ROS also play major physiological functions4,5, but it remains unknown how neuronal ROS signaling is activated during memory formation and if astrocytes play a role in that process. We discovered in Drosophila an astrocyte-to-neuron H2O2 signaling cascade essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an intracellular calcium increase that triggers the formation of extracellular O2{degrees}- by astrocytic NADPH oxidase. Superoxide dismutase 3 secreted by astrocytes converts O2{degrees}- into H2O2, which is imported into neurons of the olfactory memory center (the mushroom body), as revealed by in vivo H2O2 imaging using an ultrasensitive sensor. Importantly, SOD3 activity requires Cu2+, which we show is delivered by the neuronal Amyloid Precursor Protein. Furthermore, we found that human amyloid-{beta} peptide, involved in Alzheimers disease, inhibits the astrocytic cholinergic receptor and hampers memory formation by preventing H2O2 import into neurons. These findings could have major implications for the understanding of Alzheimers disease etiology, as soluble synaptic A{beta}42 correlates better with the pattern of cognitive decline in AD than amyloid plaques6, and since early pathology in cholinergic neurons of the basal forebrain predicts memory defects7,8.

neuroscience↗