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How may APOE impact brain changes observed in Alzheimer’s?
Abdel Ali Belaidi, Ph.D.
Florey Institute of Neuroscience and Mental Health
Parkville, Australia
Background
The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. There are several variations of the APOE gene, 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. However, it remains unclear how the ApoE protein and variations in the APOE gene may be associated with the risk of developing Alzheimer’s.
The ApoE protein interacts with several other proteins in the brain, including a protein called apolipoprotein E Receptor 2 (apoER2), however the biology by which this interaction may potentially impact brain changes observed in Alzheimer’s is not yet clear. Previously, Dr. Abdel Ali Belaidi and his colleagues identified genetic variations of apoER2 that may be associated with slower cognitive decline in individuals with Alzheimer’s. Additional preliminary findings showed that a genetic variation of apoER2 may protect brain cells from a specific kind of cell death pathway called ferroptosis, in which too much iron levels in the brain causes damage. Dr. Belaidi and his team will study how genetic variations in apoER2 may impact the vulnerability of brain cells to ferroptosis in individuals with Alzheimer’s.
Research Plan
Building on their preliminary findings, Dr. Belaidi and colleagues will further study the biology of how ApoE protein and apoER2 interact with each other. First, the researchers will grow different types of brain cells in laboratory dishes with different variations of apoER2. The researchers will then study how the different apoER2 variations may interact with APOE gene, beta-amyloid plaques, and tangles (beta-amyloid and tau proteins accumulate to form plaques and tangles respectively, two of the hallmark brain changes observed in Alzheimer’s). Based on these studies the researchers will investigate how these interactions between APOE gene, beta-amyloid plaques and tangles may impact cell death via ferroptosis. Additionally, Dr. Belaidi and colleagues will study the impact of genetically removing the apoER2 protein in two kinds of genetically engineered Alzheimer’s-like mice that have beta-amyloid and abnormal tau in their brains.
Finally, the researchers will also study the effect of the lack of apoER2 on nerve cell development and behavior in these mice.
Impact
The study results may provide insights into the impact of interplay between ApoE protein and apoER2 proteins and this interaction may be associated with brain changes observed in Alzheimer’s. If successful, the findings may help develop therapeutic targets to tackle Alzheimer’s.
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