LG3 improves the cognitive decline associated with cerebral amyloid angiopathy in APPSwDI mice

Abstract

Introduction: A common condition experienced by individuals with dementia is cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid beta (Aβ) in blood vessel walls. CAA causes the failure of intramural periarterial drainage (IPAD) which facilitates the healthy transport of nutrients and waste clearance. Perlecan is a proteoglycan with five distinct domains. Domain V is comprised of three laminin-globular-like repeats, the third of which, LG3, has been shown to be neuroprotective and angiogenic in experimental ischemic stroke and neuroprotective and angioprotective against Aβ in vitro. We hypothesized that LG3 would increase the prevalence and activity of transporters such as p-glycoprotein (Pgp) that clear Aβ from the brain. Methods: 6-month-old CAA-model APPSwDI mice were administered with intraperitoneal injections of LG3 (6 mg/kg, n=11) or equivalent volume of PBS (vehicle, n=11), every 3 days over a period of 5 weeks. Cognitive tests of Y-Maze and Morris Water Maze (MWM) were performed post treatment. Following cognitive testing, brains were collected and evaluated for changes in levels of Aβ (ELISA), Pgp, and Low-density lipoprotein receptor-related protein 1 (LRP1, western blot). In addition, isolated rodent brain microvessels were exposed to LG3 at 300 and 600nM. Pgp transport activity was determined by measuring accumulation of fluorescent Pgp substrate NBD- cyclosporine A (NBD-CSA) in the lumen of microvessels, as was the transport of fluorescent Aβ1-42, using confocal microscopy. Results: LG3 treatment marginally improved cognitive results compared to vehicle-treated controls. Aβ1-40 was reduced by LG3 treatment (non-significant trend). LG3 treatment caused elevation in Pgp and LRP1 transporters (non-significant trends). Subgroup analysis of mice with above average levels of Pgp and LRP1 was performed to determine whether LG3 influenced activity of transporters when high levels were present. LG3 treated mice had significantly improved results in MWM, particularly on days 2 and 3. Finally, LG3 treatment of brain microvessels significantly increased the Pgp mediated transport of NBD-CSA as well as Aβ transport into the vessel lumens. Discussion: LG3 may, upon dose optimization and larger n, improve the clearance of Aβ from the brain by enhancing Pgp activity and restoring IPAD functionality, thereby alleviating the effects of CAA and vascular dementia.