A novel hybrid protein promotes Aβ clearance and reduces inflammatory response through MerTK

Abstract

Alzheimer’s disease (AD) is the world’s leading cause of dementia and the most common neurodegenerative disorder. Its major pathological features are amyloid beta (Aβ) plaques, tau tangles, and neuroinflammation that eventually leads to massive death of nerve cells. Even with the multifactorial aspect of AD, the most accepted theory is that Aβ is the driving force of AD pathogenesis. We engineered a novel hybrid protein that facilitates the phagocytosis of Aβ and redirect its clearance to the noninflammatory Mer tyrosine kinase (MerTK) pathway. The novel hybrid protein facilitates robust uptake and clearance of Aβ in BV2 microglia through MerTK receptor with reduced production of inflammatory factors and oxidative products. In APP/PS1 transgenic AD mouse model, intraperitoneal administration of the hybrid protein for two months results in significant reduction of Aβ burden in the brain and protection of nerve cells from dying. Taken together, our results suggest that the novel hybrid may have the potential for AD treatment by targeting both Aβ clearance and reduction of inflammation.

MerTK mediates the immunologically silent uptake of alpha-synuclein fibrils by human microglia

“…Bispecific antibodies and hybrid proteins with affinities to both MerTK and amyloid beta have been designed to specifically target amyloid beta to MerTK- mediated, immunologically silent phagocytosis in Alzheimer’s disease. 75, 76 Similar strategies could be adopted to enhance α -syn clearance in synucleinopathies.…”