In vivo Ca ²⁺ imaging of astrocytic microdomains reveals a critical role of the amyloid precursor protein for mitochondria

The investigation of amyloid precursor protein (APP) has been mainly confined to its neuronal functions, whereas very little is known about its physiological role in astrocytes. Astrocytes exhibit a particular morphology with slender extensions protruding from somata and primary branches. Along these fine extensions, spontaneous calcium transients occur in spatially restricted microdomains. Within these microdomains mitochondria are responsible for local energy supply and Ca ²⁺ buffering. Using two-photon in vivo Ca ²⁺ imaging, we report a significant decrease in the density of active microdomains, frequency of spontaneous Ca ²⁺ transients and slower Ca ²⁺ kinetics in mice lacking APP. Mechanistically, these changes could be potentially linked to mitochondrial malfunction as our in vivo and in vitro data revealed severe, APP-dependent structural mitochondrial fragmentation in astrocytes. Functionally, such mitochondria exhibited prolonged kinetics and morphology dependent signal size of ATP-induced Ca ²⁺ transients. Our results highlight a prominent role of APP in the modulation of Ca ²⁺ activity in astrocytic microdomains whose precise functioning is crucial for the reinforcement and modulation of synaptic function. This study provides novel insights in APP physiological functions which are important for the understanding of the effects of drugs validated in Alzheimer's disease treatment that affect the function of APP.