Dopamine and Sigma Receptor Mixed Modulators for the Treatment of Alzheimer's Disease

An estimated 1-in-8 individuals over the age of 65 has Alzheimer’s disease (AD), with a prevalence of 1-in-3 for those over age 85. There are approximately 5.8 million people in the USA with AD, with a global projection of over 150 million by 2050. Given the limited state of therapeutic options, a viable therapeutic approach that is not redundant with current medications would be of great benefit to AD patients and caregivers. Sigma receptors (σ1 and σ2) and dopamine receptors (D2 and D3) have been respectively attracting attention as brain targets for Alzheimer’s disease (AD) treatment. We have developed a small molecule (AM73) with affinity for σ1/σ2 and D2/D3 receptors. This mixed modulator approach is novel and presents a viable means to treat cognitive decline and associated symptomology. This proof-of-concept study evaluates the mixed modulator AM73 in a mouse model of cognitive decline and AD. Aims of the study focus on determining the effect of chronic treatment of AM73 across a dose-response respective to behavior and locomotor responses in male and female mice. Key brain regions associated with AD pathology and targeted receptors will be evaluated for changes in mRNA and protein expression respective to pathological indicators and treatment markers. The goal and aims of this study address priorities of National Institute on Aging.