Alzheimer’s disease (AD) is a complex disease with poorly understood mechanisms, that lead to progressive neurodegeneration, with symptoms including the destruction of memory and thinking skills, and, in later stages, the inability to carry out the simplest tasks. AD is the most common cause of dementia among older adults, contributing to as many as 60-70% of cases.1 Characterized by the loss of neurons and synapses in and around the cerebral cortex, many theories have been proposed on the cause and mechanism of disease progression; however, there are no approved pharmacologic treatments for AD that will slow or stop the damage and destruction of neurons. Amyloid beta (Aβ) and Tau protein misfolding and aggregation are strongly associated with neurodegeneration in Alzheimer’s disease patients, with many therapies targeting aggregate depletion as a means to delay or reverse the advancement of symptoms.2,3 While preclinical rodent models suggest degrading or reducing these protein aggregates improves AD symptoms, the same has not been shown in humans.
The receptor protein tyrosine phosphatase sigma (PTPσ) is a promising target for reducing the clinical effects of Alzheimer’s disease, with several preclinical studies supporting this hypothesis. PTPσ is expressed in neural stem cells, progenitor cells including oligodendrocyte progenitor cells (OPCs), oligodendrocytes, astrocytes, neurons and microglia/macrophages.4,5,6,7 Chondroitin sulfate proteoglycans (CSPGs), a type of glycoprotein often found in areas of the body where neuronal growth is limited, bind and signal predominantly through PTPσ, which in turn inhibits neuronal growth, sprouting, plasticity and regeneration.4 Supporting the potential role of PTPσ inhibition is evidence seen in knock-out models of PTPσ. Genetic depletion of PTPσ in AD models suppressed Aβ accumulation, tau aggregation, neuroinflammation, and synaptic loss, while enhancing behavioural and cognitive function including spatial navigation and memory, and novel object recognition.8
Furthermore, Alzheimer’s disease and general cognitive impairment is associated with upregulation of CSPGs in the cerebral cortex, increasing as cognition declines even prior to AD onset.9 In AD mouse model studies, enzymatic digestion of CSPGs with chondroitinase (ChABC) enhanced neural plasticity and improved AD outcomes. For example, cortical injection of ChABC in AD model mice reduced Aβ burden, reversed loss of synaptic density surrounding plaques and restored long-term potentiation and cognition.9,10,11
Neuronal pathology and axonal injury are major contributors to progressive and permanent disability in AD patients. Modulating PTPσ has the potential to alter AD pathology by promoting regeneration at areas of nerve damage, plasticity in intact areas of the brain and by dampening Aβ production.