2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

Probing Vulnerability in Circuits for Social Behavior in FTD

What kinds of brain changes help explain how social isolation may promote one’s risk for frontotemporal dementia?

Kristen Berendzen, Ph.D.
University of California, San Francisco
San Francisco, CA - United States

Background

Research suggests that social behavior may be closely linked to the maintenance of brain health. Some studies have linked certain social behavior characteristics (including being married, having a larger social network size and frequently engaging with friends) with preserved cognitive function during aging; while others have found that social isolation may be a risk factor for Alzheimer’s and other dementias. Researchers, however, do not yet understand the exact biological mechanisms that link social isolation and dementia risk. This lack of knowledge is due, in part, to the difficulty of studying social isolation in animal models.

Dr. Kristen Berendzen and colleagues have been working with prairie voles, an animal model that does develop human-like social attachments and monogamous male-female partnerships (or pair bonding). They have engineered voles with a genetic variation that reduces activity in a gene called granulin. Altered granulin function has been associated with both Alzheimer’s and frontotemporal dementia (FTD), a brain disease in which individuals can develop particularly severe forms of social isolation. In preliminary studies, the researchers found that their engineered voles are less able to maintain stable monogamous relationships, a feature also seen in humans with FTD.  

Research Plan

Dr. Berendzen and team will now use their vole model to conduct a larger study of how social isolation is linked to brain changes in frontotemporal dementia. First, they will examine various brain regions in voles that have been socially isolated for 4 weeks and voles that have remained socially active. This work will involve measuring disease-related accumulations of TAR DNA-binding protein 43 (TDP-43), a hallmark protein in FTD, as well as changes in the activity of immune cells called microglia. Microglia normally remove unwanted or damaged components in the brain, but altered microglial activity can lead to harmful protein build-up and brain cell damage. 

The investigators will take samples of blood and cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord) from the voles at different stages of development. They will look for abnormal levels of neurofilament light chain (NfL) and other FTD-related proteins in the samples, and determine whether such changes take place at the time the animals begin to exhibit antisocial behavior. Lastly, Dr. Berendzen and colleagues will test whether drug compounds designed to increase granulin levels in the brain can prevent or reverse social behavior deficits in the engineered voles.     

Impact

Dr. Berendzen’s project could shed new light on brain changes underlying the relationship between social isolation and dementia. Such work could lead to novel therapies for frontotemporal dementia, Alzheimer’s disease and other brain disorders.