ABSTRACT
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aß25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aß25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
Subject(s)
Aggression/drug effects , Alzheimer Disease/drug therapy , Cognitive Dysfunction/drug therapy , Glycogen Synthase Kinase 3/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Apoptosis/drug effects , Behavior, Animal/drug effects , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/pathology , Neuroprotective Agents/therapeutic use , Phosphorylation/drug effects , Primary Cell Culture , Rats , Spinal Cord/drug effects , Spinal Cord/pathology , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies.