Perlecan Domain V as a therapeutic VCID strategy for the clearance of amyloid beta from the brain in cerebral amyloid angiopathy - PROJECT SUMMARY/ABSTRACT Vascular contributions to cognitive impairment and dementia (VCID) encompass a spectrum of cerebrovascular changes seen in small vessel diseases of the brain including cerebral amyloid angiopathy (CAA) where pathologic amyloid beta (Aβ) protein accumulates in the walls of cerebral capillaries and arteries. With increasing age, and with hyperlipidemia in early to mid-life, there is a failure of clearance of Aβ along the walls of cerebral capillaries and arteries resulting in CAA. One of the key mechanisms for the elimination of Aβ from the brain is along the extracellular matrix (ECM)-composed basement membranes of capillaries and arteries, as intramural periarterial drainage (IPAD). Aging, among other factors, changes the structure of the ECM, resulting in the failure of IPAD of Aβ. Furthermore, cerebrovascular remodeling and angiogenesis may represent early compensatory changes to the reduced blood flow seen in VCID and occur in part by increasing the proteolytic turnover of the surrounding ECM such as perlecan. We have demonstrated that perlecan domain V (DV) protein greatly reduces amyloid toxicity while enhancing angiogenesis. Human CAA patients showed a lack of perlecan staining only on amyloid positive vessels. Collectively, these studies offer striking evidence to suggest a critical role of perlecan in cerebrovascular Aβ deposition and its associated deleterious effects. Lastly, proteoglycans can have effects on endothelium transporter mechanisms such as P- glycoprotein (P-gp) which are vital to Aβ elimination from the brain, which also fail with age. This increased burden on IPAD correlates to blood-brain barrier (BBB) disruption, ultimately worsening Aβ deposition in the brain, which contributes to VCID. As cerebrovascular basement membranes change with age, interventions upon the ECM that improve IPAD may represent an early, critical, and therapeutically relevant approach for the prevention of CAA and VCID. Here we hypothesize that DV plays an important endogenous role in vascular clearance of Aβ which can be therapeutically exploited in IPAD-related changes in VCID. In support of this hypothesis, preliminary data suggest that: 1. DV increases hAβ clearance by increasing P-gp expression and activity in cerebral microvessels in vitro, 2. DV increases hAβ transit across WT mice-derived BECs in vitro, 3. mice that express 10% of total normal perlecan and DV levels (referred to as Pln-/-) have impaired IPAD as determined by a higher number of capillaries and arterioles with Aβ in their walls (compared to Aβ-injected WT controls) after stereotactic injection of Aβ, and 4. Pln-/- - derived BEC’s have deficient Aβ transit that can be rescued by DV treatment in vitro. Armed with these results, we propose to analyze DV-mediated increased clearance of Aβ across brain endothelial cells in mechanistic detail, and to determine the role and therapeutic potential of DV on IPAD of Aβ and experimental CAA.
