What is the role of apolipoprotein receptor 2, a protein found in the brain vessels, in Alzheimer’s disease ?

The brain vascular system is critical to supply the necessary energy and control the transport of molecules in and out of the brain. Failure of this system is seen early in Alzheimer’s disease, is linked to memory loss and makes the brain more vulnerable to toxic aggregates like amyloid-beta. Improving brain vascular function might be beneficial for people diagnosed with Alzheimer’s disease. However, the cause behind the failure of the brain vessels in Alzheimer’s disease is still largely unknown. My preliminary results show that a protein expressed in the brain vasculature, apolipoprotein receptor 2, is reduced in the brain of people diagnosed with Alzheimer’s disease and people at high risk for the disease. Lower levels of this protein are linked to cerebral amyloid angiopathy, a disease that impairs vessels function, and to to poor memory. Interestingly, the role of this protein in the brain vasculature is still undefined. I will use an approach combining genetically modifed mouse models, imaging of awake mice, memory test and assays on post-mortem mouse tissue to uncover the function of this protein in brain vessels. First, I will remove the protein from the brain vessels of the mice to see if brain vessel are still able to control cerebral blood flow and transport of molecules in the brain. Next, I will increase the expression of the protein in a mouse model of Alzheimer’s disease to see if it reduces cerebral amyloid angiopathy and improves memory. Finaly, I will increase the levels of the protein in brain vessels of mice with a human risk factor of Alzheimer’s disease (apolipoprotein E4) to see if it improves vessel function. Together, these experiment will constitute the first step to see if apolipoprotein receptor 2 could be a good therapeutical target to improve brain vessels function in Alzheimer’s disease patients.