Investigation of Novel Purinergic Therapeutics for the Treatment of Alzheimer’s Disease and Amyotrophic Lateral Sclerosis

Abstract

Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are complex age-related neurodegenerative diseases. Due to the poorly understood pathomechanisms of each disease, current treatment options are limited with only a few clinically approved therapeutics. Considering the absence of a clinically-approved disease-altering therapeutic, there is an ever-growing need to identify new therapeutic targets. A common hallmark of both AD and ALS is the presence of neuroinflammation as a product of an increased immune response from the brain’s resident immune cells, astrocytes and microglia. The purinergic system contributes greatly to neuroinflammation elicited by these cells, particularly through the P2X7R, P2X4R and P2Y6R. These receptors are upregulated in states of disease and have been implicated as drivers of neuroinflammation and dysregulated autophagy and phagocytosis. Despite the reported therapeutic potential of antagonising these receptors there are no clinically-approved antagonists. A lack of relevant pre-clinical models highlights the problems and difficulties of developing a therapeutic for neurodegenerative diseases like AD and ALS. The discovery of induced pluripotent stem cells (iPSCs) provides a novel platform for pre-clinical research, allowing relevant human cell types like astrocytes and microglia to be derived. These cells retain the genetic make-up of the healthy control or AD and ALS donors. This thesis sought to advance the field of purinergic therapeutics for use in AD and ALS by conducting structure-activity relationship studies for novel candidate P2X7R, P2X4R and P2Y6R antagonists to deepen the understanding of key structural features that impart potency. Secondly, this thesis utilised iPSC-derived glial cells to understand the nature of cell autonomous purinergic receptor expression and functionality in ALS and AD, with a view towards establishing a new translational model for in vitro purinergic drug discovery for these diseases.