Targeting alpha synuclein and amyloid beta by a multifunctional, brain-penetrant dopamine D2/D3 agonist D-520: Potential therapeutic application in Parkinson’s disease with dementia

Abstract

Abstract A significant number of people with Parkinson’s disease (PD) develop dementia in addition to cognitive dysfunction and are diagnosed as PD with dementia (PDD). This is characterized by cortical and limbic alpha synuclein (α-syn) accumulation, and high levels of diffuse amyloid beta (Aβ) plaques in the striatum and neocortical areas. In this regard, we evaluated the effect of a brain-penetrant, novel multifunctional dopamine D2/D3 agonist, D-520 on the inhibition of Aβ aggregation and disintegration of α-syn and Aβ aggregates in vitro using purified proteins and in a cell culture model that produces intracellular Aβ-induced toxicity. We further evaluated the effect of D-520 in a Drosophila model of Aβ1-42 toxicity. We report that D-520 inhibits the formation of Aβ aggregates in vitro and promotes the disaggregation of both α-syn and Aβ aggregates. Finally, in an in vivo Drosophila model of Aβ1-42 dependent toxicity, D-520 exhibited efficacy by rescuing fly eyes from retinal degeneration caused by Aβ toxicity. Our data indicate the potential therapeutic applicability of D-520 in addressing motor dysfunction and neuroprotection in PD and PDD, as well as attenuating dementia in people with PDD.