Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia.

Amanda L Trout,Gregory J Bix,Ibolya Rutkai,Ifechukwude J Biose

doi:10.3390/ijms21020679

Abstract

Perlecan is a heparan sulfate proteoglycan protein in the extracellular matrix that structurally and biochemically supports the cerebrovasculature by dynamically responding to changes in cerebral blood flow. These changes in perlecan expression seem to be contradictory, ranging from neuroprotective and angiogenic to thrombotic and linked to lipid retention. This review investigates perlecan’s influence on risk factors such as diabetes, hypertension, and amyloid that effect Vascular contributions to Cognitive Impairment and Dementia (VCID). VCID, a comorbidity with diverse etiology in sporadic Alzheimer’s disease (AD), is thought to be a major factor that drives the overall clinical burden of dementia. Accordingly, changes in perlecan expression and distribution in response to VCID appears to be injury, risk factor, location, sex, age, and perlecan domain dependent. While great effort has been made to understand the role of perlecan in VCID, additional studies are needed to increase our understanding of perlecan’s role in health and in cerebrovascular disease.

Highlights

The basement membrane (BM) is a thin layer of extracellular matrices (ECMs) that anchors the epithelium, mesothelium, and endothelium to the underlying smooth muscle and connective tissue [1,2]
DI contains a Sperm, Enterokinase and Agrin fold with GAG and heparan sulfate (HS) attachment sites that has been proposed to facilitate the release of heparan binding growth factors in wound healing [33,34,35]
Truncated perlecan DI, found in Hspg2−/− or perlecan knock out mice, has been associated with complete loss of function, embryonic lethality (~E10–12), enlarged ventricles, smaller brains, and weakened vasculature leading to severe bleeding and heart malformations [24,25,37]

Summary

Extracellular Matrix and Perlecan

The basement membrane (BM) is a thin layer of extracellular matrices (ECMs) that anchors the epithelium (e.g., respiratory tract), mesothelium (e.g., peritoneal cavity), and endothelium (e.g., vasculature) to the underlying smooth muscle and connective tissue [1,2]. DI contains a Sperm, Enterokinase and Agrin fold with GAG and heparan sulfate (HS) attachment sites that has been proposed to facilitate the release of heparan binding growth factors in wound healing [33,34,35] This domain has a distinct, perlecan specific protein motif that does not share homology with any other proteins [36]. The third laminin G-like subdomain (LG3) appears to be bioactive and may convey much of DV’s reported biological activity [18,20] Overall, these observations provide strong evidence that perlecan is essential for brain, bone, heart, and cartilage development and plays a critical role in the maintenance of homeostatic balance in the brain following injury

Perlecan and the Cerebrovasculature in Disease and Stroke

Findings

Conclusions