AbstractBackgroundProgranulin (PGRN) is a secreted pleiotropic growth factor primarily expressed in neurons and microglia that regulates neuroinflammation, neurite branching and outgrowth. PGRN has been identified as a Cathepsin D chaperone, suggesting a role in lysosomal proteolysis. PGRN together with Prosaposin (PSAP) have been proved to be physiologically involved in lysosomal lipid catabolism. PSAP physically interacts with PGRN and facilitates glycosphingolipid degradation upon lysosomal processing, serving as activators of various lysosomal lipases. Thus, PGRN and PSAP play an essential role in the regulation of lysosomal homeostasis. Reduced lysosomal protein levels and activity, as well as accumulation of toxic proteins, have been observed in age‐dependent neurodegenerative diseases. The impact of the disturbance of the PGRN‐PSAP axis in these diseases is not yet fully understood.AZP2006 (INN: Ezeprogind) is a small molecule currently under development for the treatment of Progressive Supranuclear Palsy (PSP, Ph2a completed) and Alzheimer’s Disease (AD). AZP2006 was proved to protect neurons, to increase synaptogenesis and to reduce neuroinflammation in different models of proteinopathies. Importantly, its neuroprotective properties were fully abolished in absence of PGRN or PSAP. Although its exact mode of action (MOA) is still unclear, AZP2006 has been proved to target lysosomes and bind the complex PGRN‐PSAP. Considering this information, the AZP2006 lysosomal MOA was further investigated.MethodAged (18mo) C57Bl6 mice receiving Aβ1‐42 oligomers bilaterally injected into the CA1 area of the hippocampus, were orally treated (gavage) with AZP2006 (1 or 2mg/kg/day) for 22 days. At the end of the treatment, the brain, CSF and plasma of the animals were collected. Lysosomal markers were investigated (LAMP‐2, LC‐3b, PGRN, PSAP, α‐Syn and glycosphingolipids contents). Histological analysis of the CA1 hippocampal area was performed (LAMP‐2, LC‐3b and α‐Syn in neurons and microglial cells). In addition, plasma and CSF samples of PSP patients generated from PSP Ph2a were analyzed.ResultAZP2006 displayed beneficial effects in the Ab1‐42 oligomers injured aged mice. AZP2006 was able to correct the lysosomal dysfunction and to restore the lysosomal homeostasis.ConclusionAZP2006 represents an original therapeutic approach to protect the PGRN‐PSAP balance that is fundamental for the neuron health.