S4-04-06: Presenilin complex modulation of APP and notch molecule at gammma and epsilon sites

Abstract

and neuronal function. Patients with mild-to-moderate AD treated with Dimebon for one year were stabilized on measures of cognition and memory, activities of daily living, behavior and global function, while placebo-treated patients declined significantly. The magnitude and durability of clinical benefits and excellent safety and tolerability profile observed for Dimebon in Alzheimer’s patients suggests a mechanism of action (MOA) distinct from currently marketed AD drugs. Preclinical experiments confirm Dimebon’s lack of significant activity against cholinesterases and NMDA receptors, consistent with its unique MOA. Similarly, Dimebon does not appear to interact with other targets implicated in cognition and memory, including the muscarinic receptors, nicotinic receptors and phosphodiesterases. Neurodegenerative diseases such as AD are characterized by synapse loss and neuron death. A body of literature suggests that abnormal depolarization of mitochondrial membranes plays a significant role in the loss of neuron function in several neurodegenerative diseases, including AD. Results: Dimebon is a highly potent (pM to low nM) stabilizer of mitochondria as measured by JC-1 staining of primary neurons in culture. Dimebon is also a potent (pM to low nM) stimulator of neurite outgrowth in primary neurons derived from the cortex, hippocampus and spinal cord of rodents. Dimebon’s neurotrophic effects are believed to be related to its ability to stabilize, protect and enhance mitochondrial and neuronal function. Dimebon’s efficacy in animal models of memory impairment at picomolar plasma concentrations is consistent with a potent MOA. Neuroprotection measured by mitochondrial vital stains occurs within minutes to hours of Dimebon exposure, while the trophic effects on neurite outgrowth occur over longer exposures. These activities may be related to the short term and longer term effects of Dimebon seen in the completed pivotal Dimebon AD trial. Conclusions: Dimebon is a promising potential therapeutic agent for AD, with a unique and novel target, the mitochondria. The most potent activity of Dimebon identified to date is the stabilization and enhancement of mitochondrial and neuronal function.