Alzheimer's disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble ß-amyloid (Aß) plaques in the brain has long been considered central to the pathogenesis of AD. However, recent evidence suggests that soluble oligomeric assemblies of Aß may be of greater importance. Amyloid precursor protein (APP) processing yields Aβ monomers which undergo oligomerization, eventually forming amyloid fibrils and plaques. Aß oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action had remained elusive. It has recently been shown that cellular prion protein (PrP-C) is a high-affinity receptor for Aß oligomers, mediating their toxic effects on synaptic plasticity.
It is hypothesized that the Aß/PrP-C interaction leads to dendritic spine retraction via synaptotoxic action, with subsequent neuritic dystrophy and neurodegenerative pathology. These later steps are then coupled to tauopathy and memory impairment in AD. By employing biochemical analysis, in vivo imaging of dendrites, genetic investigation and behavioral studies, this hypothesis can be tested. A drug discovery program for novel AD therapeutics has been launched with PrP-C as a molecular target.
Nogo Receptor
In the adult mammalian central nervous system (CNS), nerve fibers do not spontaneously regrow due in part to the presence of myelin-associated neurite growth inhibitors such as Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). These growth inhibitors signal the Nogo-66 receptor (NgR). Bound NgR effectively inhibits axon growth in the CNS.
In recent years, scientific advancements have been published that demonstrate that axons can regrow undercontrolled environmental conditions. The use of a soluble NgR decoy receptor blocks the interaction between myelin associated neurite growth inhibitors and the myelin bound NgR, which effectively blocks the inhibition of axon growth. Axon growth has since been demonstrated in rodents with spinal cord injury(SCI), either from transection or from contusion injury. Increased axon growth has then led to increased function from animals after SCI.
At Axerion, we seek to harness the potential of surviving tissue to restore function. In nearly all neurological conditions, a substantial portion of brain and spinal cord is preserved. If remaining healthy tissue can be “rewired” with appropriate axonal connections, improved neurological function can result. The formation of new connections and the recovery of function after injury depend upon new axonal extension from remaining cells. Without treatment, axonal growth is extremely limited in the adult brain and spinal cord, and recovery is typically restricted.
Other therapeutic areas which may be impacted by blocking neurite growth inhibition include traumatic brain injury, ischemic stroke recovery, optic nerve damage and chronic progressive multiple sclerosis.
