2022 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

BMP and APOE Interactions in Astrocyte Lipid Metabolism and AD Pathology

How does APOE, an Alzheimer’s risk gene, impact the processing of fats in brain cells?

Chian-Yu Peng, Ph.D.
Northwestern University
Chicago, IL - United States

Background

Brain cells (in particular, nerve cells) need lipids (fats) for energy and for maintaining their structures. As a result, the process by which fat is produced and transported to these cells is vital for the proper function of the brain. Nerve cells receive fats from “helper” cells in the brain called astrocytes. Scientists have found that lipids can accumulate abnormally in the brain, possibly leading to the build-up of the proteins tau and beta-amyloid, which form tangles and plaques respectively, two hallmark brain changes in Alzheimer’s. 

The apolipoprotein E (APOE) gene makes ApoE protein, which is thought to help carry fats throughout the body. There are several APOE gene variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought to impact some populations’ risk of developing Alzheimer’s. However, it remains unclear how variations of the ApoE protein and the APOE gene may be associated with dementia risk.

Previous research by Dr. Chian-Yu Peng and colleagues suggest that ApoE may interact with a protein named BMP (bone morphogenetic protein) to impact lipid metabolism (the ability of brain cells to effectively process and convert fats to energy) in astrocytes. However, the mechanisms underlying this interaction, and how it may impact biological brain changes associated with Alzheimer’s, are not well understood.

Research Plan

Dr. Peng and colleagues will study how BMP and ApoE interact and impact lipid metabolism using a special kind of stem cell called induced pluripotent stem cells (iPSCs). These are created from adult human skin cells and “reprogrammed” into any kind of cell in the body, including astrocytes and nerve cells. Using astrocytes and nerve cells created from iPSCs, the research team will determine which aspects of BMP-regulated lipid metabolism are impacted by APOE. They will also study how BMP-regulated lipid metabolism may be impacted differently by different variations of the APOE gene in both astrocytes and nerve cells.

In addition, Dr. Peng and colleagues will use special genetically engineered Alzheimer’s-like mice to study whether inhibiting BMP activity in astrocytes may impact biological brain changes and cognitive decline associated with the APOE-e4 gene variation.

Impact

The findings may shed light on how gene variations may impact risk for Alzheimer’s. If successful, the results may point to novel therapeutic targets to prevent or treat Alzheimer’s, especially in individuals with genetic risk factors for the disease.