ISC 2024 | The impact of the neurovasculome on cognitive function in neurodegenerative diseases
Costantino Iadecola, MD, Weill Cornell Medical College, Cornell University, New York, NY, explains the intricate relationship between the neurovasculome and cognitive function. Prof. Iadecola emphasizes that data from single-cell studies in the Alzheimer’s disease (AD) brain versus the healthy brain reveal that approximately ⅔ of AD risk genes are vascular genes, strongly indicative of a neurovascular component underlying cognitive decline. The neurovasculome contributes to both the production and clearance of proteins like amyloid β (Aβ) and tau. For example, hypertension is thought to provoke amyloidogenic processing and impact tau phosphorylation, leading to protein accumulation. On the other hand, impaired vascular function can hinder the brain’s waste clearance mechanisms. Therefore, the disruption of the neurovasculome causes a number of pathogenic mechanisms that contribute to cognitive dysfunction in neurodegenerative diseases. This interview took place during the International Stroke Conference 2024 in Phoenix, AZ.
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Transcript (edited for clarity)
The single cell data that I was mentioning previously, both in the setting of Alzheimer disease and in normal vasculature, has revealed that the majority, about two thirds, of the Alzheimer’s risk genes which have been identified by GWAS studies are vascular genes. So this provided further evidence in support of the idea that Alzheimer’s is not just a neurodegenerative condition, but there is also a neurovascular component to the cognitive decline which may relate either to the production of amyloid-beta and tau or to their clearance...
The single cell data that I was mentioning previously, both in the setting of Alzheimer disease and in normal vasculature, has revealed that the majority, about two thirds, of the Alzheimer’s risk genes which have been identified by GWAS studies are vascular genes. So this provided further evidence in support of the idea that Alzheimer’s is not just a neurodegenerative condition, but there is also a neurovascular component to the cognitive decline which may relate either to the production of amyloid-beta and tau or to their clearance. Because vascular risk factors can increase the accumulation of tau and amyloid-beta, whereas vascular problems in the clearance end may facilitate the accumulation in the brain. So the vasculature is uniquely poised to really affect the production of those proteins as well as the clearance of the proteins. So that’s kind of the balance.
Now on the production side, there is evidence that hypertension, for example, may promote amyloidogenic processing of amyloid precursor protein leading to A-beta accumulation, you know. And hypertension is associated with more tau in the brain. We don’t know exactly how that occurs, but it is a finding and recent data using an angiotensin based hypertension model suggests that the vasculature may promote tau hyperphosphorylation by interfering with the phosphorylation mechanism that regulate tau stability in neurons. So you have the vessel influencing the phosphorylation state of tau in neurons, which is a very novel idea that his may occur in hypertension.
And now on the clearance side, vascular risk factors like ApoE4, hypertension, and so on, they impair the ability of the vessels to constrict and relax in response to activity. So neural activity generates the the waste right that you need to get rid of. All right. And the vasculature picks up that waste and dumps it into the venous system eventually into the right atrium of the heart. Now if the ability of the vessels to constrict and relax that facilitate this clearance function is affected, then you’re going to end up also getting stuck with more stuff in the brain. So you can see how the vasculature can be involved in both the degeneration of the garbage that we want to get rid of, A-beta and tau, and the clearance that is absolutely necessary because the brain doesn’t have any other way to get rid of the stuff. Everything goes through the vessels and everything comes out of the vessels or the lymphatics, you know? So through those channels, the action is going to have to take place.
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