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 (Aß) 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 Aß along the walls of cerebral
capillaries and arteries resulting in CAA. One of the key mechanisms for the elimination of Aß 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 Aß. 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 Aß 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 Aß
elimination from the brain, which also fail with age. This increased burden on IPAD correlates to blood-brain
barrier (BBB) disruption, ultimately worsening Aß 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 Aß
which can be therapeutically exploited in IPAD-related changes in VCID. In support of this hypothesis,
preliminary data suggest that: 1. DV increases hAß clearance by increasing P-gp expression and activity in
cerebral microvessels in vitro, 2. DV increases hAß 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 Aß in their walls (compared to Aß-injected WT controls) after
stereotactic injection of Aß, and 4. Pln-/- - derived BEC’s have deficient Aß transit that can be rescued by DV
treatment in vitro. Armed with these results, we propose to analyze DV-mediated increased clearance of Aß
across brain endothelial cells in mechanistic detail, and to determine the role and therapeutic potential of DV on
IPAD of Aß and experimental CAA.
