2024 New Investigator Awards Program (NIAP)
Alternative APOE transcripts and Alzheimer's disease
How may changes in the activity of a dementia-associated gene product increase one’s risk for Alzheimer’s?
Liang Ma, Ph.D.
University of Texas Health Science Center at San Antonio
San Antonio, TX - United States
Background
The apolipoprotein E (APOE) gene provides instructions for making ApoE, a protein thought to help carry lipids (fats) throughout the body. The APOE gene has several variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought in some populations to impact an individual’s risk of developing Alzheimer’s. Scientists, however, do not know exactly how APOE-e4 promotes disease risk.
To reduce this knowledge gap, Dr. Liang Ma and colleagues have been studying how APOE-e4 is made into ApoE protein, and how minute changes in this process may be linked to Alzheimer’s. In order to make a protein, a gene is turned “on” and a cell’s machinery makes a type of genetic material called ribonucleic acid (RNA), which mostly acts as a messenger between DNA (the cell’s instruction manual) and the protein. The RNA molecules that make protein are known as mRNA (or transcripts). Dr. Ma and team have analyzed brain samples from a diverse array of people who did or did not have Alzheimer’s disease, and they identified a specific APOE transcript (called jxn1.2.2) whose activity may become altered and contribute to Alzheimer’s-related brain changes in both European and African populations. The team also identified a particular segment of the APOE gene that may promote these disease-related changes in jxn1.2.2.
Research Plan
Dr. Ma and colleagues will now conduct a larger study of jxn1.2.2 and Alzheimer’s disease. First, to verify that this APOE transcript is associated with Alzheimer’s risk, they will genetically analyze brain samples from diverse individuals who did or did not have Alzheimer’s. Next, they will study how altered jxn1.2.2 activity may impact the biology of three-dimensional brain-like structures called cerebral organoids. These structures are created in the laboratory from stem cells engineered from adult human skin cells and then “reprogrammed” into brain cells. When grown in a laboratory dish under the right conditions, a group of brain cells can mimic the structure and function of brain tissue. Dr. Ma and team will change levels of jxn1.2.2 activity in these cells using a gene editing technique called CRISPR. They will then look for other segments of the APOE-e4 gene that may affect jxn1.2.2 function, and how jxn1.2.2 changes promote nerve cell damage, beta-amyloid accumulation and other brain changes of Alzheimer’s.
Impact
Dr. Ma’s project could help clarify our understanding of how people with APOE-e4 are at risk for Alzheimer’s and other dementias. Such work could lead to novel genetic therapies for these diseases.
The New Investigator Program Award (NIAP) is jointly funded by the Alzheimer's Association and National Alzheimer’s Coordinating Center.