INTRANASAL INTERVENTION OF THE LXRS-APOE-MICROGLIA AXIS TO IMPROVE BRAIN BETA-AMYLOID CLEARANCE IN A TRANSGENIC MOUSE MODEL OF AD

Abstract

The causes of sporadic forms of AD are still unresolved, and this limits the development of therapeutics strategies to treat the disease. In recent studies, the initiation and progression of AD has been linked to cholesterol metabolism, processes that can be modulated by cerebral expression of liver x receptors (LXRs). In this regard, enhanced expression of ApoE, through the activation of LXRs; facilitate the proteolytic clearance of amyloid beta from the brain. Recent in vivo studies using AD-like transgenic animal model revealed that LXRs agonists provoked inhibition of neuroinflammation, decrease cortical levels of amyloid beta and reversed memory deficits. Unfortunately, this generation of LXRs agonists causes liver steatosis and hypertriglyceridemia, limiting its clinical application. Our research is aimed to test the effectiveness of a novel LXRs agonist, called DMHCA. Unfortunately DMHCA does not cross the blood-brain barrier, thus intranasal administered dendrimer-DMHCA-FITC complex has been tested to fully describe its penetration, biodistribution and specific effects in the target areas of the mouse brain when administered for 21 days. As an alternative therapeutics approach, dendrimer-DMHCA treatment attenuates neuroinflammation, cortical oxidative stress damage and facilitate the proteolytic degradation of amyloid beta; present in our mouse model of AD; without undesirable side effects. Such studies should render suitable preclinical proof of principle for further clinical application.