Assessing the role of NOTCH3-associated clonal haematopoiesis in vascular dementia development.
Approved Research ID: 75265
Approval date: October 11th 2021
Vascular dementia (VD) is the second most frequent type of dementia. About 150,000 patients in the UK currently suffer this degenerative disease. It impacts the ability to perform daily activities. Symptoms include memory loss, slow thinking and difficulty to walk. VD worsens with time. It is caused by the damage of blood vessels in the brain which are not able to bring the oxygen and nutrients that brain cells need, leading to the death of these critical cells. The molecular mechanisms that drive VD are not well understood and there is no cure for VD.
A type of hereditary VD known as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is caused by mutations in a gene known as NOTCH3.
Interestingly, recent data (including ours) indicate that mutations in NOTCH3 that occur over the lifetime of an individual allow mutated blood and epithelial cells to accumulate and expand in healthy individuals.
Our major hypothesis is that the accumulation of NOTCH3 mutated blood cells in healthy individuals can eventually produce symptoms like those present in CADASIL resulting in VD. NOTCH3 mutated blood cells would progressively damage blood vessels by inducing increased inflammation.
Particularly, we think that in some VD patients, blood stem cells (BSC) which produce all our red and white blood cells, have acquired NOTCH3 mutations which made BSCs to divide more or die less than they should. Mutated BSCs accumulate in their bone marrow and blood without initially producing any sign of disease. This accumulation can result in a lot of their blood cells deriving from one single mutated BSC, which it is known as clonal haematopoiesis (CH). CH can be induced by mutations in other genes, especially those driving blood cancer. CH is very common in the elderly and induces a much greater risk of developing blood cancer (11-times higher) and heart diseases (three-fold higher).
This research proposal will investigate if VD patients carry CH with NOTCH3 mutations in their blood by scrutinizing the DNA sequences of VD patients and comparing them with healthy individuals which have not developed VD by the same age. We expect to complete this project within 24 months. Importantly, as there is no known cure for VD, it is mandatory to better understand how this disease arises to provide new therapeutic means for the millions of VD patients worldwide. Towards this, our research will carefully evaluate if CH could drive VD.