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How do two proteins linked with dementia risk interact with each other to cause damage to nerve cell function?
Melissa Birol, Ph.D.
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Berlin, Germany
Background
Tau protein helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau becomes modified, or “misfolded”, a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. It is uncertain how abnormal tau develops and spreads in the brain, and how tau-related brain damage takes place.
Studies have found that tau interacts with another protein called ApoE. ApoE is produced by the apolipoprotein E (APOE) gene, and it is thought to help carry lipids (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 disease.
In initial research with brain cells grown in a laboratory dish and with brain organoids (genetically engineered brain-like structures that have similar properties to human brains), Dr. Melissa Birol and colleagues have observed that tau and ApoE-e4 bind together. This binding then leads to increased levels of both ApoE-e4 and tau in nerve cell structures called lipid droplets, which help maintain normal lipid levels in the brain. Moreover, lipid activity is essential for promoting the health of synapses (the connections between nerve cells that help the cells communicate with one another). Dr. Birol’s findings suggest that tau-ApoE interactions may damage synapses, impair nerve cell communication and lead to memory loss in Alzheimer’s.
Research Plan
The researchers will study how tau and ApoE work together to impact brain health. Using cutting-edge microscope techniques they will work to visualize tau and ApoE activity. First, using brain organoids, the researchers will study how tau binds to ApoE in nerve cell lipid droplets. They will also identify what types of brain cells experience the greatest levels of lipid droplet-related tau and ApoE binding, and study how this accumulation may impact nerve cell activity. The investigators will then study in detail how the binding of tau and ApoE alter the structure of the lipid droplets, and how the distribution of bound tau-ApoE structures change over time in brain organoids.
Impact
Results from this study could shed new light on the role of tau and ApoE in brain cell function. They could also lead to novel dementia therapies that prevent abnormal tau-ApoE binding.
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