2023 Alzheimer's Association Research Fellowship (AARF)
Identifying Culprits of Capillary Stasis in Hypertensive ApoE4 Mice
How can the loss of blood flow in small brain blood vessels contribute to high blood pressure and dementia in individuals at risk for Alzheimer’s?
Lianne Trigiani, Ph.D.
Cornell University
Ithaca, NY - United States
Background
Studies show that individuals with hypertension (high blood pressure) are at significantly greater risk for cognitive decline and Alzheimer’s as they age. Research also indicates that this increased risk is even higher among individuals with APOE-e4 (ApoE4), a gene variation linked to an increased risk of Alzheimer’s in some populations; and that women with hypertension and APOE-e4 are at greater risk of brain disease than men. While scientists do not yet understand the mechanisms underlying how APOE-e4 and sex impact brain health, changes in brain blood flow may play an important role. Loss of blood flow can lower the supply of oxygen to the brain, reducing brain cell activity and leading to memory loss and other forms of cognitive decline in dementia.
In initial studies, Dr. Lianne Trigiani and colleagues examined the impact of altered brain blood flow in Alzheimer’s-like, hypertensive mice with either APOE-e4 or APOE-e3 (a gene variation not linked to Alzheimer’s risk). They found that APOE-e4 mice had greater loss of blood flow in small blood vessels called capillaries, as well as greater loss of memory and overall brain blood flow than hypertensive mice with APOE-e3. They also found that when the APOE-e4 mice received treatment to improve capillary flow, the treatment partially or fully restored the animals brain blood flow and memory. These findings confirmed the work other studies that identified capillary dysfunction as an important mechanism leading to blood flow decline and increased risk for dementia.
Research Plan
Dr. Trigiani and colleagues will now study of how capillary dysfunction, genetics and sex impact dementia risk. They will use hypertensive male and female mice with either APOE-e4 or APOE-e3. The female mice will be analyzed while undergoing perimenopause. During the perimenopausal period, women and female mice experience drops in certain hormones, including estrogen. These drops can cause certain individuals to develop hypertension and Alzheimer’s-related brain changes.
The researchers will look for changes in capillary structure that may lead to capillary blood flow loss (or capillary “stasis”) in the mice. They will then test whether capillary function – as well as brain blood flow and memory – can be restored by giving a blood thinning drug called prasugrel. Dr. Trigiani’s team will also examine the role that overactive microglia (the resident immune cells of the brain) might play in capillary stasis, and whether blood thinning treatment may promote capillary and brain health by inhibiting microglial function.
Impact
Results from this study could shed new light on the mechanisms linking high blood pressure and Alzheimer’s, especially in populations most vulnerable to the disorder. They could also lead to novel dementia treatments and prevention strategies that target capillary function.