My name is Kelsey Campbell, I’m a second-year graduate student in the department of neuroscience, and I’m working in Dr. Daniel Lee’s lab studying the effects of impacted nutrient signaling in Alzheimer’s disease (AD). I grew up in south-eastern Kentucky, and there I witnessed how a dementia diagnosis was capable of altering the dynamics of my family. By elementary school I knew that this disease was responsible for altering the independence and personality of the person I loved, and also my other family members as they took on the role of caregiver. This is a shared story amongst hundreds of thousands of people across Kentucky and the US, and unfortunately the experience is only going to become more common, as AD prevalence is increasing across the country. This increase in AD prevalence as lifespans increase highlights how crucial the need for research and developments in AD are. My research aims to understand how nutrient signaling effects accumulation and clearance of neurodegenerative pathology in AD, and if autophagic or lysosomal pathways can be exploited to reduce AD pathology.

My research project focuses on a receptor named GPRC6a, which is capable of activation by nutrients most commonly found in red meat and dairy such as arginine, lysine, and ornithine. GPRC6a has four haplotypes in humans which govern degree of insertion of the receptor at the plasma membrane. Some haplotypes have higher prevalence in certain ethnic populations, and some have an early stop codon which implies a non-functional receptor. My preliminary work has investigated the mechanism of the early stop codon in a mouse model with high tau load, and whether individuals with one allele of GPRC6a have changes in AD pathology from individuals that have two. My initial data shows that tau pathology is reduced in those mice with a heterozygous deletion of GPRC6a, which has proven GPRC6a to be a potential therapeutic target in treating AD. There are also drugs that exist for reducing activation of GPRC6a, which I will be using in my coming experiments to further investigate how GPRC6a suppression effects AD pathology.

We still have a lot to learn about GPRC6a and its role in AD. We know that GPRC6a signals nutrient status to the mechanistic target of rapamycin complex 1 (mTORC1), which is a protein that controls cells size, protein synthesis, and protein degradation. If nutrients are available GPRC6a signals to mTORC1, which will increase cell size and protein synthesis. The opposite happens when nutrients are depleted: inactivated mTORC1 will increase protein clearance. The goals of my research project include determining if GPRC6a signaling to mTORC1 is disrupted in AD, and if increased protein clearance by mTORC1 can mitigate the effects of AD. I’m excited to discover the answers to these questions in my coming years of training with the department of neuroscience and Sanders-Brown Center on Aging.