2023 Alzheimer's Association Research Fellowship (AARF)
Apolipoprotein Receptor 2 in AD-Related Brain Vessel Dysfunction
How may a certain binding protein in blood vessels be related to blood vessel dysfunction in Alzheimer’s?
Milène Vandal, Ph.D.
University of Calgary
Calgary, Canada
Background
Blood vessels in the brain provide nerve cells with oxygen-rich blood that is necessary for the cells’ ability to function properly. Inadequate blood flow can damage and eventually kill cells anywhere in the body, but the brain is especially vulnerable. Studies show that loss of brain blood vessel (or cerebrovascular) function may also represent an early brain change in dementia. These vascular changes may be associated with nerve cell damage and death observed in Alzheimer’sor other dementia. Research has also shown that a type of cell called endothelial cells may be involved. Endothelial cells line blood vessels and help transport blood, nutrients and oxygen into the brain and transport harmful proteins (such as dementia-related beta-amyloid and tau) out of the brain. However, the exact nature of endothelial cell involvement in Alzheimer’s remains uncertain.
In initial studies, Dr. Milène Vandal and colleagues studied a receptor (or binding protein) in endothelial cells called apolipoprotein E receptor 2 (ApoER2). This protein binds to several other proteins, including ApoE4. The gene that codes for ApoE4, APOE-e4, has been shown to increase risk of Alzheimer’s in some populations. Dr. Vandal’s team found that in individuals with Alzheimer’s, brain blood vessels had lower levels of endothelial ApoER2 and higher levels of beta-amyloid (a hallmark brain change in Alzheimer’s). Amyloid accumulation in brain blood vessels, known as cerebral amyloid angiopathy (CAA), is a disorder that often occurs in individuals with Alzheimer’s. Such findings indicate a role for ApoER2 in Alzheimer’s-related cerebrovascular disease.
Research Plan
Dr. Vandal and colleagues will use genetically engineered Alzheimer’s-like mice which develop low levels of endothelial ApoER2. First, they will determine how the loss of ApoER2 impacts brain blood flow and the health of the blood brain barrier (BBB, a specialized structure that helps maintain a healthy brain environment by tightly regulating what goes into and out of the brain from the circulating blood). They will then examine how reduced ApoER2 promotes the risk of CAA and cognitive decline in the mice.
Impact
Dr. Vandal’s study could shed new light on the mechanisms underlying cerebrovascular disorders in Alzheimer’s and other dementia. It could also lead to novel dementia therapies that target ApoER2.