Maintenance of Amyloid-beta Homeostasis by Carbenoxolone Post Aβ-42 Oligomer Injection in Rat Brain

Abstract

The equilibrium between cerebral production and clearance of Aβ is maintained either by the active removal through blood-brain barrier or by the uptake and degradation through ubiquitin-proteasome system (UPS) and autophagy. The dysfunction of UPS and dysregulation of molecular chaperones such as heat shock proteins (HSPs) is well correlated with the progression of Alzheimer's disease (AD). Therefore, the restoration of heat shock system and UPS appears to be an effective approach to maintain the Aβ homeostasis. The alteration in the Aβ homeostasis was induced by a single bilateral intrahippocampal injection of Aβ 42 oligomers (10 μl/rat) into the dorsal hippocampus of the rat brain. Cbx (carbenoxolone), a HSP inducer and Aβ 42 aggregation inhibitor, was tested (20 mg/kg body weight, i.p. for six-weeks) against the altered Aβ homeostasis in the rat brain. Aβ 42 oligomers downregulated the expression of HSPs and co-treatment with Cbx prevented this decline. Cbx was able to restore the UPS function post Aβ 42 oligomer injection. Aβ 42 oligomers induced upregulation of the expression levels of APP, BACE-1 and Tau was also normalized after the co-treatment with Cbx. A significant decrease in the thioflavin-T and Aβ positive deposits in different regions of the rat brain was observed after Cbx co-treatment. Thus, the present study projects Cbx as a potential candidate for the maintenance of Aβ homeostasis through inhibition of amyloid aggregation and restoration of the functioning of molecular chaperones and UPS system in the progression of AD.

Keywords: Alzheimer’s disease; BACE-1; amyloid-beta 1–42 oligomers; carbenoxolone; heat shock proteins; ubiquitin–proteasome system.