Jessika Royea, Montreal Neurological Institute
Supervisor: Edith Hamel, Montreal Neurological Institute
The majority of demented patients display mixed Alzheimer’s disease (AD) and vascular pathology encompassing various cerebrovascular alterations. AD patients have reduced resting cerebral blood flow and functional hyperemia, and deficits in cerebrovascular reactivity and autoregulation. Investigating disease- modifying therapies that address both neuronal and vascular dysfunctions in AD uphold significant potential for its prevention. The risk of developing AD increases with the number of vascular risk factors, with hypertension being the main cardiovascular risk factor. Individuals in midlife have a 90% lifetime risk of developing hypertension. Of interest, studies have shown that midlife hypertensive patients have a higher conversion rate (8-9%) to AD than healthy elderly controls. Knowing that hypertension is modifiable, it’s treatment represents an opportunity for the prevention of AD. Cohort studies have demonstrated lower incidence and progression of AD in elderly individuals treated by antihypertensive medications targeting the renin angiotensin system (RAS), including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).
Dr. Hamel’s cerebrovascular research program aims to understand the relationship between the cerebral circulation and the loss of cognitive function in AD. In addition to ageing, the most common risk factors for sporadic, prevalent form of AD are hypertension, hypercholesterolemia, and diabetes, all characterized by their vascular pathology. For my project, we are interested in understanding how medications targeting hypertension can reduce the onset and incidence of AD. My doctoral projects utilize the antihypertensive medication losartan, a commonly prescribed medication, to antagonize the angiotensin II type 1 receptor (AT1R). Losartan administration has previously been shown to normalize cerebrovascular and memory deficits in an AD mouse model (APP J20 mice). Whether the angiotensin II type 2 receptor (AT2R) or insulin-regulated aminopeptidase (IRAP, also known as the angiotensin IV receptor (AT4R)) mediates the beneficial effects of the AT1R needs to be addressed.
Our first results obtained during my MSc used a selective IRAP antagonist to attempt to prevent the benefits obtained by losartan treatment. Interestingly, our results showed that IRAP antagonism prevented memory and cerebrovascular benefits during losartan treatment. I look forward to determining the role of the AT2R in mitigating losartan’s beneficial effects to further comprehend how angiotensin receptor blockers (ARBs) are able to lower the incidence of cognitive decline and decrease the rate of AD progression. Overall, we seek to decipher the mechanism of action specifying how ARBs prevent cerebrovascular and memory deficits in AD. Our research could identify targets for the development of a new class of drug analogs that may act as cognitive and cerebrovascular enhancers, and act as a new avenue for AD treatments.