Slowing prion disease via M1 muscarinic receptors is associated with reduced neuroinflammation and down-regulation of neurodegenerative disease markers

Currently there are no treatments that can slow or halt the progression of dementia’s including Alzheimer’s disease. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which shows many of the pathological hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulated as well as a normalisation in the expression of markers associated neurodegeneration and Alzheimer’s disease. Furthermore, synaptic proteins and post-synaptic signalling components disrupted in disease are maintained by VU846. We conclude that allosteric regulation of M1-receptors have the potential to reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.