2024 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Apolipoprotein E receptors as drug targets in Alzheimer's disease

Can apolipoprotein E receptors or related molecules be drug targets for Alzheimer's disease treatment?

Abdel Ali Belaidi, Ph.D.
Florey Institute of Neuroscience and Mental Health
Parkville, Australia

Background

Genes play an important role in Alzheimer’s and for most individuals who have late-onset Alzheimer’s, the genetic mechanisms are not well understood. The most prominent genetic variation thought to increase risk in some populations for late-onset Alzheimer’s is APOE-e4; a gene which provides instructions for making ApoE protein; ApoE helps carry fats throughout the brain and body. There are several variations of the APOE gene, including APOE-e2, APOE-e3, and APOE-e4.  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). Previously, Dr. Abdel Ali Belaidi and 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 high iron levels in the brain leads to damage. Dr. Belaidi and team will study how genetic variations in apoER2 may impact other molecules and progression of  Alzheimer’s with the goal of identifying potential drug targets.

Research Plan

Dr. Belaidi and colleagues will study how a variation  in the apoER2 gene, called SNP RS5174, interacts with other molecules in nerve cells. The researchers will grow human derived brain cells in laboratory dishes with this specific variation in apoER2 and see how it impacts cell death, ferroptosis, and molecules that are hallmarks of Alzheimer’s (amyloid beta, tau, and phospho-tau). They will also find out what communication networks (signaling pathways) it may influence.

Additionally, Dr. Belaidi and colleagues will identify molecules that interact with apoER2 SNP RS5174 using rat nerve cells grown in laboratory dishes. They will then study whether these molecules can help protect the nerve cells. Finally, the researchers will study the effect of apoER2 SNP RS5174 in genetically engineered Alzheimer’s-like mice and how it impacts accumulation of hallmark Alzheimer’s proteins, neurodegeneration, and disease progression compared to genetically engineered Alzheimer’s-like mice without apoER2.

Impact

The study results may provide insights into the impact of a protein (apoER2 SNP RS5174) that is potentially protective against Alzheimer’s as well as molecules that it interacts with and may help it have a positive impact. If successful, the findings may help identify therapeutic targets to tackle Alzheimer’s.