Lipid Peroxidation and APOE Variants in Alzheimer's Disease
Researchers here report on the role of lipid peroxidation in the pathology of Alzheimer's disease, in particular as a way to explain why some variants of apolipoprotein E (APOE) appear to be linked to a greater risk of developing this neurodegenerative condition. Alzheimer's is a complex biological failure state built of many interdependent chains of cause and effect, and thus the one small area touched on in this research, somewhere in the midst of this sea, can be linked to a range of other processes and failures observed in the brain tissue of patients and animal models. To pick a few examples: rising levels of inflammation and oxidative stress; the failure of lysosomes - and thus failure to recycle metabolic waste - in the glial support cells in the brain; and also the changing behavior and generally greater dysfunction of these glial cells with increasing age.
Researchers discovered in 2015 that a number of genes involved in neurodegeneration promote damage to neurons and glia by inducing high levels of free radicals (oxidative stress) and accumulation of lipid droplets in glia. This work sets the stage for the current study. "Using electron microscopy, we observed lipid droplet accumulation in glia before obvious symptoms of neurodegeneration. In the presence of high levels of oxidative stress, neurons produce an overabundance of lipids. The combination of free radicals and lipids, which produces peroxidated lipids, is detrimental to cellular health. Neurons try to avoid this 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 and providing a protective mechanism."
The team discovered that the storage of lipid droplets in glia protects neurons from damage as long as the free radicals do not destroy the lipid droplets. When the lipid droplets are destroyed, cell damage and neurodegeneration ensues. "Our research brought us to a fascinating and unexpected finding. Approximately 15 percent of the human population carries apolipoprotein APOE4. Since APOE4 was first linked to Alzheimer's disease almost 30 years ago, it remains the strongest known genetic risk factor for this disease. Meanwhile, APOE2, which is slightly different from APOE4, is protective against the disease. This evidence suggests that APOE is important for proper brain function, but we know little about how APOE itself may lead to Alzheimer's disease".
The researchers found that apolipoproteins APOE2, APOE3 and APOE4 have different abilities to transfer lipids from neurons to glia and hence differ in their ability to mediate the accumulation of lipid droplets. "APOE2 and APOE3 can effectively transfer lipids into glia. On the other hand, APOE4 is practically unable to carry out this process. This results in a lack of lipid droplet accumulation in glia and breakdown of the protective mechanism that sequesters peroxidated lipids. This fundamental difference in the function in APOE4 likely primes an individual to be more susceptible to the damaging effects of oxidative stress, which becomes elevated with age."