Biology subjects

Falzoni, S.

Publications and source records attributed to Falzoni, S..

3 recordsLinked to original sources

bioRxiv2025

The extracellular ATP/P2X7R signaling axis drives early neuroinflammation and neuronal hyperexcitability in an Alzheimer's disease mouse model

Neuroinflammation and synaptic dysfunction are emerging as early and potentially causative events in Alzheimers disease (AD), yet their molecular triggers remain elusive. Here, we identify extracellular ATP (eATP), a major damage-associated molecular pattern, and its purinergic receptor P2X7 (P2X7R) as pivotal drivers of early pathology in AD mice. In vivo bioluminescence imaging revealed a significant cortical accumulation of eATP in AD mice as early as 2 months of age--before amyloid plaque deposition and cognitive impairment. This increase is associated with inflammasome activation, pro-inflammatory cytokine production, microglia reactivity, aberrant synaptic pruning and perineuronal net degradation. Strikingly, genetic deletion of P2X7R rescues these alterations. Two-photon calcium imaging further demonstrates that P2X7R knockout counteracts AD-related neuronal hyperactivity. These findings set the eATP-P2X7R signaling axis as an early driver of AD pathology, linking neuroinflammation to synaptic remodeling and circuit dysfunction, and suggest P2X7R inhibition as a compelling strategy to counteract AD progression.

neuroscience↗

bioRxiv2023

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

Microparticles (MPs) are ubiquitously secreted by all cells and play a fundamental role in numerous biological processes such as cell-to-cell communication, cell differentiation, inflammation, and cell energy transfer. Ligation of the P2X7 receptor (P2X7R) by extracellular ATP (eATP) is the well-known stimulus for MP release, which affects their contents in a cell-specific fashion. We investigated MP release and functional impact in mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) expression of the P2X7R. Stimulation with extracellular ATP triggered a P2X7R-dependent release of a MP population enriched with naked mitochondria. Released mitochondria were taken up and incorporated into the mitochondrial network of the recipient cells in a P2X7R-dependent fashion. Other constituents of the MP cargo, e.g. NLRP3 and the P2X7R itself, were also delivered to the recipient cells. Transfer of mitochondria, NLRP3 and P2X7R increased the energy level of the recipient cells and conferred a pro-inflammatory phenotype. These data show that P2X7R-dependent exchange of MPs and mitochondria modulates energy metabolism and inflammatory responses, pointing to the P2X7R as a master regulator of intercellular organelle and MP trafficking in mouse microglia.

cell biology↗

bioRxiv2020

The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance

Basal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, ATP synthesis and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack a) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca2+ level, b) modifies expression pattern of oxidative phosphorylation (OxPhos) enzymes, and c) severely affects cardiac performance. Hearts from P2rx7-deleted versus WT mice are larger, heart mitochondria smaller, and stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and cardiac output (CO), are significantly decreased. Accordingly, physical fitness of P2X7R-null mice is severely reduced. Thus, the P2X7R is a key modulator of mitochondrial energy metabolism and a determinant of physical fitness.

cell biology↗