You've recently published a paper in Nature Aging about the role of APOE4, a variant of apolipoprotein E associated with Alzheimer's disease, on vascular function and neurodegeneration. Could you explain the main findings of the study and what you think the implications are for studying the mechanisms of neurodegenerative disease?
By introducing a form of APOE associated with a higher risk of Alzheimer’s, APOE4, into a mouse model of the disease, we observed leakier blood vessels in the brain and faster progression of the disease. Looking deeper into the mechanism, APOE4 is unable to interact with an important receptor found on pericytes, which usually triggers signalling pathways that protect the blood-brain barrier.
Instead, the pericytes activate an inflammatory pathway, involving the molecule cyclophilin A, which leads to key components of the barrier being degraded. We found a drug that inhibited cyclophilin A and, amazingly, we were able to restore the barrier function in the mouse model of disease. The results are showing us that we can actively target the blood-brain barrier with treatments for brain health and dementia.
Do you think that research into the dysfunction of the blood-brain barrier that occurs during neurodegenerative disease could potentially lead to advancements in diagnosis of these conditions?
We have ways to do brain imaging with MRI and look at the blood-brain barrier. The problem is that blood-brain barrier dysfunction is not specific to Alzheimer's disease. That would be too easy. It's very common in many dementias, such as cerebral small vessel disease, Parkinson's disease and multiple sclerosis.
We know that blood-brain barrier function is very important, and we have ways to measure this by looking at certain biomarkers in blood samples and cerebrospinal fluid. Additionally, together with MRI scans, we are looking at these blood-brain barrier markers over a long time in people at risk of developing Alzheimer's disease and trying to see whether we can predict cognitive decline or brain changes. These methods now have to be validated on bigger cohorts of people living with dementia.
Montagne, A., Nikolakopoulou, A.M., Huuskonen, M.T. et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nat Aging 1, 506–520 (2021).
Article published: 27 September 2021
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