Neuroprotective & Alzheimer’s disease risk genes


The brain has a natural protective mechanism against Alzheimer’s disease, and researchers at Baylor College of Medicine, Texas Children’s Hospital and collaborating institutions have discovered that gene variants associated with risk of developing the disease disturb the protective mechanism in ways that can lead to neurodegeneration. The researchers also showed in a fruit fly model of the condition that a chemical known as ABCA1 agonist can restore certain alterations of the brain protective mechanism.

The team reveals evidence supporting reactive oxygen species (ROS), natural byproducts of cellular metabolism linked to inflammation and other processes, as key players in events leading to the disruption of the neuroprotective mechanism. In addition, the researchers found that ROS, together with amyloid-beta, the main component in the plaques found in the brains of people with Alzheimer’s disease, accelerated disease development in animal models. Altogether, the findings provide new mechanistic insight into factors involved in Alzheimer’s disease development, supporting the idea that multiple alterations at the genetic and other cellular levels combine to induce the disease. The study appears in the Proceedings of the National Academy of Sciences.

“Previous work conducted by Dr. Lucy Liu in Dr. Hugo Bellen’s lab and colleagues showed that two brain cell types, neurons and glia, work together to protect against neurodegeneration,” said first author Dr. Matthew Moulton, a postdoctoral associate in the Bellen lab. “In the current study, we worked with fruit fly and mammal models to investigate whether known genetic risk factors for Alzheimer’s disease were associated with disturbing the protective mechanism, diving deep into the details of how this happened.”

The neuroprotective mechanism is engaged when neurons face high levels of ROS, which stimulates neurons to produce abundant lipids. ROS levels increase with aging, different forms of stress or because of genetic factors. The combination of ROS and lipids produces peroxidated lipids, which deteriorate cellular health. Neurons try to avoid the damage by secreting these lipids, and apolipoproteins, proteins that transport lipids, carry them to glia cells. Glia store the lipids in lipid droplets, sequestering them from the environment, thus keeping them from damaging neurons.

In the previous work, the researchers connected the neuroprotective mechanism to the strongest genetic risk factor for Alzheimer’s disease, apolipoprotein APOE4. “We found that APOE4 is practically unable to transfer lipids to glia, while other two forms of APOE, APOE2 and APOE3, carry out the transfer effectively,” said Bellen, Distinguished Service Professor of molecular and human genetics at Baylor. “With APOE4, lipid droplet accumulation in glia is drastically reduced and the protective mechanism breaks down. This fundamental difference in the function in APOE4 likely primes an individual to be more susceptible to the damaging effects of ROS, which becomes elevated with age.”

Read more