Silvia Anderle, PhD, University College London, London, UK, discusses her work looking at the interactions between APOE4 and vascular function in the emergence of Alzheimer’s disease (AD) pathology. As well as being the strongest genetic risk factor for AD, the APOE4 allele is associated with hypercholesterolemia and ischemic heart disease. It has therefore been suggested that the vascular dysfunction associated with APOE4 may play a role in making the brain more vulnerable to AD development. Using in vivo two-photon microscopy in mouse models, Dr Anderle assessed blood flow and neuronal activity. Mice expressing APOE4 showed impairments in blood vessel responsiveness to neuronal activity, meaning there was a mismatch between energy needs and supply. It is thought that long-term mismatch could contribute to neuronal damage by increasing hypoxia and facilitating toxic protein aggregation. This interview took place at The BNA 2023 International Festival of Neuroscience in Brighton, UK.
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Transcript (edited for clarity)
So APOE4 is the strongest genetic risk factor for Alzheimer’s disease. So APOE is normally involved in the lipid and cholesterol metabolism and the gene comes in three forms APOE2, APOE3 and APOE4. But it’s the APOE4 isoform of the gene that is associated with the increased risk and is not only APOE4 associated with increased risk of Alzheimer’s disease but also with an increased risk of vascular dysfunction...
So APOE4 is the strongest genetic risk factor for Alzheimer’s disease. So APOE is normally involved in the lipid and cholesterol metabolism and the gene comes in three forms APOE2, APOE3 and APOE4. But it’s the APOE4 isoform of the gene that is associated with the increased risk and is not only APOE4 associated with increased risk of Alzheimer’s disease but also with an increased risk of vascular dysfunction. So people that have the APOE4 gene are more prone to develop conditions such as hypercholesterolemia, hypertension and blood-brain-barrier breakdown. So there seems to be a link there between vascular dysfunction induced by APOE4 and the development of Alzheimer’s disease.
So what we are trying to understand in our research is how this vascular dysfunction that is induced by APOE4 can actually make the brain more vulnerable to develop Alzheimer’s disease. And what we have found is that in preclinical mouse models that have either the APOE3 or the APOE4 gene, the mice that have the APOE4 gene are more likely to develop vascular dysfunction. So they have blood vessels that are not able to respond adequately to the energy needs of the of the neurons. Therefore, because of this lack of responses and this impairment in the way that the vessels respond, the neurons are not receiving enough nutrients and energy for them to be healthy and to function properly. So there is a mismatch between energy needs of the neurons and energy supply. And we believe that in the long term, after many years of this situation being in place, this causes a long-term damage to the neurons and increases situations like hypoxia, So increase of deficiency in oxygen in the brain which is known to cause more damage and also facilitate the aggregation of toxic proteins and accumulation of those. So it is very important to understand how vascular dysfunction happens, what is going on and try and find ways to prevent it from happening.