2024 Alzheimer's Association Research Grant (AARG)
Deciphering Early AD Progression via Olfactory System and AQP4 Dynamics
Why do people with Alzheimer’s often experience changes in their sense of smell?
Michele Dibattista, Ph.D.
Università degli Studi di Bari Aldo Moro
Bari, Italy
Background
There are several hallmark brain changes associated with Alzheimer’s. These include the accumulation of proteins such as beta-amyloid plaques and tau tangles in the brain. In cognitively unimpaired individuals, the glymphatic system successfully removes waste products and excess proteins, using a collection of water channels located in and around brain cells that help to “flush out” waste. Emerging research suggests that problems with the glymphatic system might contribute to protein accumulation in the brain during Alzheimer’s.
One of the common early symptoms of Alzheimer’s is loss of smell. Smell is transmitted to the brain via different nerve cells and structures, collectively known as the olfactory system. Previous research by Dr. Michele Dibattista and others has identified several variations in a water channel (called aquaporin-4, or AQP4) that is found on olfactory nerve cells. More research is needed to understand how these variations might impact olfactory or glymphatic system functioning in Alzheimer’s.
Research Plan
For the current study, Dr. Dibattista and colleagues will explore how different AQP4 variations might help to protect nerve cells from protein accumulation in the brain during Alzheimer’s. They will use mice genetically engineered to have different AQP4 variations and Alzheimer’s-like disease. First, the researchers will analyze olfactory structures collected from the mice at different stages of disease progression. They will use specialized microscopes to determine the kinds of cells that comprise the olfactory systems in the mice. Next, they will test the function of olfactory structures, by exposing nerve cells in laboratory dishes to odors and measuring nerve cell electrical responses.
In a second part of the study, the researchers will determine if AQP4 variations affect the ability of cerebral spinal fluid (CSF, the fluid that surrounds the spinal cord) to “flush out” waste products during Alzheimer’s. Dr. Dibattista’s team will compare beta-amyloid and tau protein levels in brain tissue samples collected from the Alzheimer’s-like mice with different AQP4 variations. Then, they will inject a dye into the CSF of live mice and use specialized brain scans to track how CSF flows through the glymphatic system. They will also expose the genetically engineered mice to external smells to understand if activating the olfactory system might lead to faster CSF flow. Their goal is to determine how AQP4 variations might contribute to changes in smell or protein clearance in the brain during Alzheimer’s.
Impact
Results from this study could help connect two biological changes that can occur in Alzheimer’s: accumulation of beta-amyloid or tau proteins in the brain, and disruption of a person’s sense of smell. The findings may also point to intervention strategies (such as sensory stimulations) or new therapeutic targets (AQP4 channels on nerve cells) for drugs designed to delay or prevent these hallmark changes that can occur in Alzheimer’s.