2022 Alzheimer's Association Research Fellowship (AARF)

A Spatial Transcriptomic Approach to Interrogate Vascular-Associated Microglia in AD

How do aging and neurodegeneration impact interactions between immune cells and blood vessel cells in the brain?

Violeta Duran Laforet, Ph.D.
University of Massachusetts Chan Medical School
Worcester, MA - United States

Background

Aging is one of the largest risk factors for Alzheimer’s. Several biological mechanisms may contribute to the risk associated with aging. One of these is an aging process called senescence, during which cells become unable to divide. Studies show that with aging, senescent cells tend to accumulate in the brain  and may be associated with the release of proteins related to brain inflammation. 

Brain inflammation is also associated with a dysregulation of the immune cells in the brain. Microglia are the primary immune cells of the brain and help maintain healthy nerve cells. However, overactivation of microglia can lead to brain inflammation. In Alzheimer’s, microglia can increase their activity and damage nearby nerve cells. Additionally, as individuals age, blood vessels can become damaged. This is a problem that impacts blood flow in the brain and may impact an individual’s risk for Alzheimer’s and other dementias.
 
A subset of microglia, called juxtavascular microglia (JVM), directly contact vascular (blood vessel) cells and impact their function. Although about 20% of all microglia are JVM, little is known about microglia-vascular interactions in cognitively unimpaired aging and in Alzheimer’s.

Research Plan

Dr. Violeta Duran Laforet and colleagues will study how JVM are impacted by aging and neurodegeneration and if these changes occur in brain areas more vulnerable to nerve cell death. 
First, the researchers will study the activity of genes associated with JVM in genetically engineered Alzheimer’s-like mice. They will use a new technique called MERFISH (multiplexed error robust fluorescence in situ hybridization) that will allow them to map and label vascular cells and types of microglia in the brain, as well as distinguish between senescent and non-senescent cells.
 
Next, Dr. Laforet and colleagues will use MERFISH to study JVM cells in brain tissue from individuals who had Alzheimer’s or mild cognitive impairment (MCI, a subtle type of memory loss that may precede Alzheimer’s) and individuals who were cognitively unimpaired. The team will obtain brain tissue from the Massachusetts Alzheimer’s Disease Research Center tissue bank. Their sample will include individuals aged 65-75 years and 80-90 years, to study the impact of aging on these JVM cells. Dr. Laforet and team will determine the number and location of JVM in different brain regions and then study how their gene activity changes and is impacted by aging, senescence, inflammation, and Alzheimer’s.

Impact

This study may contribute to our understanding of the interactions between aging, the vascular system, and brain immune cells in Alzheimer’s. The results may influence the development of novel therapeutics that target brain immune cells to prevent or treat Alzheimer’s.