Revisiting the vascular contribution to Alzheimer’s Disease
Alzheimer’s Disease (AD) is the most common cause of failing memory in the elderly and is characterized by the accumulation of Aß peptides within brain tissue, where they form amyloid deposits. Over 60% of AD patients have apolipoprotein E4 (apoE4), which prolongs Aß half-life and causes earlier and more aggressive amyloid deposition. The vast majority of AD patients also have Aß deposits in cerebral blood vessels, which is called cerebral amyloid angiopathy or CAA and compromises cerebrovascular function. One way that amyloid-forming Aß peptides leave the brain is by drainage along the brain’s blood vessels. In healthy people, Aß drains efficiently. However, in AD, Aß peptides get stuck within the brain’s blood vessels, which may eventually impair cerebral blood flow and starve neurons.
Apolipoprotein A-I (apoA-I) is a component of plasma “good cholesterol” that selectively reduces CAA and improves memory in AD mice. Although apoA-I is not produced in the brain, it is present in cerebrospinal fluid at levels typically at 0.1% of its plasma concentration. We have previously shown that the cholesterol transporter ABCA1 enhances the beneficial functions of apolipoproteins including apoA-I and apoE. We have also shown that drug candidates including Liver-X-Receptor (LXR) agonists increase ABCA1 activity, reduce amyloid burden and improve memory in AD mice. However, because ABCA1 is expressed throughout the body and because systemic administration of LXR agonists will enhance apoE function in the brain and apoA-I function in plasma, we do not yet know whether the efficacy of LXR agonists for AD is due mainly to ABCA1 activity on apoE to promote Aß degradation within brain tissue itself, or on peripheral apoA-I to remove Aß from the cerebrovasculature. This is a crucial question, as it is not known whether increasing the function of apoE4 may be beneficial or harmful for AD patients.
Our proposed studies will test whether genetic or drug-based methods that specifically enhance Aß drainage from the brain’s blood vessels via apoA-I can prevent AD in mice. This work may provide a novel therapeutic approach for AD that works from the inside of blood vessels and will be safe for all AD patients
Dr. Cheryl Wellington was one of the exceptional scientists identified to be a research grant recipient in the 2013 Alzheimer Society Research Program (ASRP) competition, co-funded by The Pacific Alzheimer Research Foundation (PARF) and the Alzheimer Society of Canada (ASC). > Learn more…