AZP2006/EZEPROGIND neuroprotective effect in age-related cognitive decline and Alzheimer's disease progression.

Abstract

AZP2006/EZEPROGIND is a disease-modifying small molecule that is currently in clinical development for the treatment of Progressive Supranuclear Palsy (PSP). Here we investigated its neuroprotective effect on in vitro and in vivo models of Alzheimer's disease (AD). We showed that AZP2006/EZEPROGIND neuroprotective action is mediated by Progranulin (PGRN) and correlated with a reduction of neuroinflammation. Primary rat cortical neurons cultured with microglia were injured with Aβ1-42 oligomers. We investigated the effect of AZP2006/EZEPROGIND on neuronal survival and neurite network (MAP2), synapses (PSD95/SYN), pTau (AT100), microglia activation (OX-41), neuroinflammation (IL-1β and IL-6) and PGRN levels. The PGRN mediated effect of AZP2006/EZEPROGIND was assessed by blocking Ab anti PGRN and siRNA for PGRN and/or Prosaposin (PSAP). AZP2006/EZEPROGIND (3 mg/kg/day) was also orally administered to the Senescence Accelerated Mouse-Prone 8 (SAMP8) mice, a spontaneous animal model of accelerated aging, from the age of 2, 4 or 6 months to 10 months. Learning and memory deficits were evaluated by Y-Maze Test and by Passive Avoidance Test. PGRN levels and of biochemical markers of oxidative stress (LPO), pTau (T181), Aβ1-42 , proinflammatory cytokines (IL-1β and IL-6), neuronal (NeuN) and microglial (Iba1) markers were studied by ELISA and IHC. In vitro, nM concentrations of AZP2006/EZEPROGIND significantly increased the neuron survival, the neurite network and the number of synapses. The incubation with blocking Ab anti PGRN and siRNA for PGRN and/or PSAP abolished these effects. Also, AZP2006/EZEPROGIND significantly decreased Tau hyperphosphorylation and reduced the neuroinflammation. The chronic treatment with AZP2006/EZEPROGIND significantly increased the Spontaneous Alternation in the Y-Maze Test and the Step-through Latency in the Passive Avoidance Test. We showed that AZP2006/EZEPROGIND was able to protect neurons, enhance synaptic function, decrease the hyperphosphorylation of Tau and reduce the neuroinflammation via PGRN. The chronic oral treatment was able to prevent, protect and restore the aged-related cognitive decline in the SAMP8 mice. We postulate that neuroprotective properties of AZP2006/EZEPROGIND not only could delay the progression of AD but also has the potential to reverse aged-related cognitive damages.