, the William K. Warren, Jr. Professor of Medicine and director of Vanderbilt University鈥檚 鈥�, and , founding director of the WCNDD and professor emeritus of pharmacology, have contributed seminal work to a study that has identified a new treatment for previously untreatable dementias, including Alzheimer鈥檚 disease.听
Many dementias, including Alzheimer鈥檚, take over the brain through the spread of 鈥減rion-like鈥� misfolded proteins. With their long-term collaborators at the University of Glasgow, Lindsley and Conn discovered that activating the M1-receptor鈥�a key brain protein involved in memory and learning鈥攃ould reduce molecular markers of neuroinflammation and adaptive processes associated with prion-mediated neurodegeneration.
鈥淭丑别 M1 receptor in particular, with its high expression in memory centres and pro-cognitive properties, has been proposed as a target for treating memory loss in Alzheimer鈥檚 disease that would avoid the dose-limiting, adverse responses associated with current clinically approved cholinesterase inhibitors,鈥� according to the study.听听
To activate the M1 receptor in mice, a small molecule positive allosteric modulator tool compound is delivered to the brain through oral dosing. The tool, VU846, is 鈥�an excellent proof-of-concept M1-receptor PAM to broadly assess the pre-clinical benefits of selective M1 activation,鈥� according to the study. Both the M1-receptor PAM approach and the key compound, VU846, were pioneered by Lindsley, Conn and the WCNDD.听
Broadly, the purpose of a PAM is to bind to a target receptor to change its response to the endogenous agonist and potentiate its effects. In this case, selective potentiation of the M1 receptor successfully diminished neuroinflammation and normalized abnormal neurotransmission, both hallmarks of neurodegeneration. According to the study, this work 鈥�provides support for the M1 receptor as an attractive therapeutic target to potentially reduce neurodegenerative disease severity and maintain synaptic function, thereby increasing lifespan and maintaining neurological function.鈥澨�听
鈥淭his is a very important moment, as we genuinely have the prospect of not only treating the symptoms of Alzheimer鈥檚 disease, including memory loss, but that we might actually be able to slow the disease and increase the lifespan of sufferers from neurodegenerative diseases like Alzheimer鈥檚 disease,鈥� Lindsley said.听
鈥淭his is an exciting moment in this program. We have long had strong evidence that M1 PAMs would improve cognitive function in patients with Alzheimer鈥檚 disease and related disorders,鈥� Conn said. 鈥淭丑别 current studies provide compelling evidence that these drugs could also reduce progression of these devastating diseases.鈥澨�听
Lindsley and Conn鈥檚 teams are testing an M1 PAM in humans in collaboration with Acadia Pharmaceuticals.听
The study, 鈥�鈥� was published in the journal Science Signaling in November 2022. The work was funded in part by a Wellcome Trust collaborative award.听听
