Sagar, N. | bioRxiv Science

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↗

bioRxiv2021

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington disease

Huntingtons disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntingtons disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntingtons disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntingtons disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntingtons disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntingtons disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

neuroscience↗