2023 Alzheimer's Association Research Fellowship (AARF)
Neuronal Circuits Underlying Apathy in Alzheimer's Disease
Can nerve cell changes in a brain region linked to emotion and motivation promote apathy in Alzheimer’s?
Guang-Wei Zhang, Ph.D.
University of Southern California
Los Angeles, CA - United States
Background
Alzheimer’s and other dementia are progressive disorders, and individuals often develop neuropsychiatric symptoms such as agitation, depression, and apathy, as well as memory loss. Apathy can reduce social interaction and lower motivation for disease treatment. In addition, apathy has been linked to accelerated rates of cognitive decline in individuals with dementia. Studies of apathy and dementia, however, are relatively small in number, and more research is needed to better understand how apathy affects brain health in individuals living with Alzheimer’s.
In initial studies with genetically engineered Alzheimer’s-like mice, Dr. Gwang-Wei Zhang and colleagues have been examining the molecular mechanisms underlying dementia-related apathy. They found that their mice had apathy-like behaviors, as well as certain disease-associated changes in the septum, a brain region involved in regulating emotion and motivation. The researchers also found that such changes may have involved certain nerve cells in the septum called GABAergic neurons. GABAergic neurons express gamma-aminobutyric acid (GABA), a neurotransmitter (or chemical messenger) that normally helps prevent nerve cells from becoming overactive. Taken together, these findings suggest that apathy in dementia may result, in part, from dysfunction in septal GABAergic nerve cells.
Research Plan
Dr. Zhang and colleagues will now clarify the underlying mechanisms of dementia-related apathy. They will use a variety of mouse models engineered to develop Alzheimer’s-like brain changes. First, they will assess how different types of Alzheimer’s-like mice develop apathy over time. They will then examine how apathy and cognitive decline are related in the animals. Next, the researchers will examine GABAergic nerve cell changes in the septum, and determine how these changes impact the development of apathy in both male and female animals.
Impact
Results from this study could shed new light on how apathy develops in dementia and how it may contribute to dementia progression. They could also lead to novel dementia therapies that target GABAergic nerve cells in the septum.