Activation of M1 muscarinic receptors reduce pathology and slow progression of neurodegenerative disease

The most prevalent types of dementias, including Alzheimer9s disease, are those that are propagated via the spread of 9prion-like9 misfolded proteins. Despite considerable effort, no treatments are available to slow or stop the progression of these dementias. 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 we show here displays many of the pathological, behavioural and biochemical 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 dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer′s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has 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.