2024 New Investigator Awards Program (NIAP)
Uncovering Mechanisms APOE Genotype-Mediated Alzheimer’s Disease Risk
How does a dementia-related gene variation help generate harmful tau protein in Alzheimer’s disease?
Jessica Schwarz, Ph.D.
Icahn School of Medicine
New York, NY - 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.
Dr. Jessica Schwarz and colleagues have been studying APOE-e4 and dementia risk in a three-dimensional brain-like structure called a multi-cellular integrated Brain (miBrain). This structure was created in their laboratory with induced pluripotent stem cells (iPSCs), which were engineered from adult human skin cells and then “reprogrammed” into a variety of brain cells, including nerve cells, astrocytes (“helper” cells) and microglia (immune cells). The miBrain is able to mimic the structure and function of natural brain tissue. Preliminary results from these studies found that astrocytes with APOE-e4 promote the formation of disease-related tau. Accumulation of abnormal tau has been shown to promote brain cell damage and memory loss in Alzheimer’s. The researchers also found that APOE-e4 astrocytes have high levels of PLIN2, a protein involved in tau processing. In addition, the astrocytes contained abnormal levels of proteins related to exosomes (fluid-filled spheres that help transport proteins and other substances between brain cells). This latter finding suggests that APOE-e4 astrocytes may promote abnormal tau clumping by releasing exosomes with high levels of abnormal tau molecules.
Research Plan
Dr. Schwarz and colleagues will devote their research grant to verifying and expanding on their earlier results. First, using iPSC-derived astrocytes, they will clarify whether APOE-e4 promotes higher levels of PLIN2 protein in astrocytes, and how these increased PLIN2 levels may promote excessive production of abnormal tau. They will also explore how APOE-e4 may enable astrocytes to release high levels of abnormal tau through exosomes. Lastly, Dr. Schwarz and team will use their miBrain technology to examine how the release of abnormal tau from astrocytes may lead to tau accumulation (and tau disease) in nerve cells.
Impact
Dr. Schwarz’s project could help clarify our understanding of the role of APOE-e4 in dementia-related tau clumping. Such work could lead to novel dementia therapies that target APOE-e4 astrocytes.
The New Investigator Program Award (NIAP) is jointly funded by the Alzheimer's Association and National Alzheimer’s Coordinating Center.