2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Decoding the molecular principles of Apolipoprotein E proteinopathy

How does a protein linked to Alzheimer’s cause problems in the brain?

Martin Marek, PhD
Fakultní nemocnice u sv. Anny v Brne (St. Anne`s University hospital in Brno)
Brno, Czech Republic

Background

Genes play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein, which is thought to play a role in processing lipids (fats), metabolism, and the brain’s immune system. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. In some populations, the APOE-e4 variation is thought to increase a person’s risk of developing Alzheimer’s, whereas APOE-e2 seems to protect against Alzheimer’s.

Recent research indicates that the ApoE-e4 protein may form toxic clumps, much like the Alzheimer’s hallmark brain changes, formed by the proteins amyloid-beta and tau. Additionally, ApoE can be broken down into smaller pieces and these smaller pieces may contribute in a harmful way. One way these fragments may contribute to Alzheimer’s is by interacting with genetic material (DNA) to turn “on” or “off” certain genes. However, these processes are not well understood.

Research Plan

Dr. Martin Marek and colleagues will utilize a technique called X-ray crystallography, which involves the crystallization of proteins into a solid structure, and then using x-rays to shoot at the crystal and use the way the light bounces off the crystal to generate a pattern. This will help the team then perform computational reconstruction of the proteins’ 3-dimensional structure. The researchers will use this method to study the 3-dimensional structure of ApoE clumps to map spots on the protein that are more likely to clump or aggregate together. If the research team can then block these spots with drugs, they might be possible to prevent clumping.

They will also study how different ApoE protein variations, both those that are protective against Alzheimer’s and those that are associated with Alzheimer’s, have different patterns of light through this method. The methods being used by the team will be able to identify places along the proteins that are more likely to be cut or spliced in the cell. Knowing where they are broken into pieces could help them design drugs that block this fragmentation.

To help identify possible drugs to block this clumping, the team will use virtual screening to narrow down options, then test the candidate molecules in a specialized type of stem cells called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body and grown in laboratory dishes. They will use iPSCs derived from people with Alzheimer’s to measure the effects of the candidate molecules on ApoE-e4 behavior.

Impact

Results of this study could improve our understanding of the biological mechanisms that drive changes that are observed in Alzheimer’s, especially those linked to APOE gene variations. It may also identify new potential targets for therapeutics.