2024 Alzheimer's Association Research Fellowship (AARF)
Sex-specific vulnerability mediated by Parvalbumin neurons in Alzheimer's disease
Do specialized nerve cells in the brain contribute to Alzheimer’s differences in males and females?
Arnaldo Parra-Damas, Ph.D.
Universitat Autonoma De Barcelona
Bellaterra, Spain
Background
According to the 2024 Alzheimer’s Association Facts & Figures report, of the 6.9 million Americans with Alzheimer’s, nearly two-thirds are women. However, the mechanisms that contribute to these sex differences in Alzheimer’s remain unclear. In Alzheimer’s, nerve cells in the brain become overly excited (a toxic process called excitotoxicity), leading to nerve cell death and cognitive decline. Recent studies have shown that parvalbumin (PV) neurons, a specialized type of brain cell that helps prevent nerve cells from becoming overactive, undergo changes during Alzheimer’s progression and likely contribute to excitotoxicity and memory loss. Additionally, PV neurons play a key role in to sex-specific differences in cognition and emotion.
In preliminary studies, Dr. Arnaldo Parra-Damas and colleagues found that female genetically engineered Alzheimer’s-like mice have increased levels of impaired PV neurons compared with male mice. For their project, the researchers will build on this observation and examine the mechanisms by which PV neurons contribute to sex differences in Alzheimer’s.
Research Plan
Dr. Parra-Damas and the team will use both female and male genetically engineered Alzheimer’s-like mice that develop amyloid plaques and tau tangles (two of the hallmark brain changes in Alzheimer’s) for their studies. First, they will use an advanced sequencing technique called transcriptomics (the study of how genes are turned “on” or “off” within a cell) to examine the sex-specific differences in gene activity in the PV neurons of these mice. They will also identify the specific regions of the hippocampus (a region of the brain that plays a key role in learning, memory, and emotions) where PV neuronal gene activity and their relationship to amyloid plaque and tau tangle levels differs between sexes. Next, the researchers will identify whether the same differences in PV neurons are also observed in brain tissue from females and males who had Alzheimer’s. Lastly, the team will use behavioral and cognitive assessments to evaluate the therapeutic potential of altering PV neuronal activity in female genetically engineered Alzheimer’s-like.
Impact
Results of this study may uncover the underlying biological mechanisms that put women at a higher risk for developing Alzheimer’s. If successful, the findings may support larger studies to evaluate the therapeutic potential of targeting PV neuronal activity in those at greater risk of developing the disease.