In vivo Ca²⁺ imaging of astrocytic microdomains reveals a critical role of the amyloid precursor protein for mitochondria

Abstract

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, APPdependent 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. K E Y W O R D Samyloid precursor protein, astrocyte, in vivo Ca 2+ imaging, microdomain, mitochondria fragmentation

Echinacoside Suppresses Amyloidogenesis and Modulates F-actin Remodeling by Targeting the ER Stress Sensor PERK in a Mouse Model of Alzheimer’s Disease

“…Increasing target activity is often less effective than inhibiting that of a certain target for disease treatment. APP has a variety of normal physiological functions, so inhibiting its synthesis will cause certain side effects (Dawkins and Small, 2014;Montagna et al, 2019). In the present study, no significant difference in the expression of the full-length APP was detected between ECH-and vehicle-treated 2 × Tg-AD mice, indicating that ECH did not decrease Aβ production by inhibiting the synthesis of APP.…”

“…A potential concern about our data is that ECH-decreased Aβ production may be due to the reduction in the APP level. In view of the fact that APP protein has many normal physiological functions (Dawkins and Small, 2014;Montagna et al, 2019), depressing its production will result in some adverse consequences. We sought to definitively exclude this possibility by assessing the full-length APP (flAPP) protein level in the brain of mice with or without ECH treatment.…”

Amyloid, APP, and Electrical Activity of the Brain

“…These alterations of spine morphology might contribute to impaired spine plasticity as thin spines are less stable. This is supported by the finding that 5 weeks exposure to an enriched environment has no effect on spine density in APP-KO mice, while physiologically enhancing it in controls (Montagna and others 2019; Zou and others 2016).…”

“…In a recent study full-length APP was found to play a critical role in mitochondrial calcium homeostasis in astrocytes. In vivo Ca 2+ imaging of astrocytic microdomains revealed a critical role of the amyloid precursor protein for mitochondria (Montagna and others 2019). As astrocytes potently modulate neuronal function by regulating the local supply of ions and energy metabolites, these findings point toward a novel, APP-related mechanism modulating brain function via glial cells.…”

“…The unexpected discovery of the η-secretase pathway (Willem and others 2015) after three decades of research on APP demonstrates how much is still to be explored. Importantly, APP is not confined to neurons, but is ubiquitously expressed und thus is also suggested to affect the function of astrocytes, microglia, other immune and endothelial cells (Montagna and others 2019). It is likely that APP does also influence brain function via its effects in non-neuronal cells.…”