Scientists at the Baylor College of Medicine, Texas Children’s Hospital, and collaborating institutions say they have discovered that gene variants associated with the risk of developing Alzheimer’s disturb the brain’s protective mechanism in ways that can lead to neurodegeneration. The team also showed in a fruit fly model of the condition that a chemical known as ABCA1 agonist can restore certain alterations of the neuroprotective mechanism.
The research, “Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease–associated genes,” published in the journal Proceedings of the National Academy of Sciences (PNAS), also 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 appear to 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.
“A growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induce lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent” write the investigators.
“To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP. Our data also show that ROS enhances Abeta42 phenotypes in flies and mice.
“Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.”
“Previous work conducted by Lucy Liu, PhD, in Hugo Bellen’s lab and colleagues showed that two brain cell types, neurons and glia, work together to protect against neurodegeneration,” said first author, Matthew Moulton, PhD, 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, which 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,” explained Bellen, DVM, PhD, 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.”
“In the current work, we wanted to identify genes that are critical for lipid droplet formation, specifically genes that are required for lipid export from neurons and lipid import into glia,” noted Moulton. “We looked at genes that interact with APOE in neurons to get the lipids out, and also in glia to get the lipids in. One reason we are interested in this comes from human studies that show that genes involved in both import and export of lipids have been implicated in Alzheimer’s disease and other related conditions.”
“In all cases in which ROS was present and we saw droplet loss, we also saw neurodegeneration, again supporting that perturbations in glia droplet formation can lead to neuronal damage,” Moulton added.
With this approach, the team demonstrated that several genes that genome wide sequencing studies had associated with risk of developing Alzheimer’s disease disturbed neuroprotective lipid droplet formation, providing a mechanism that can explain the risk associated with these genes.
In addition, using the fruit fly model, Moulton and his colleagues tested whether an ABCA1 agonist, which was previously shown to restore APOE4’s ability to transfer lipids, could enable APOE4 to mediate lipid droplet formation in glia in the fruit fly model. “The ABCA1 agonist restored glial lipid droplet formation in an APOE4 fruit fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity,” said Bellen, chair in neurogenetics in the Jan and Dan Duncan Neurological Research Institute at Texas Children’s.
The researchers also investigated whether ROS could exacerbate the effect amyloid-beta may have on the disease.
“We observed that ROS and amyloid-beta together increased neuronal death in fruit flies and resulted in larger and more numerous amyloid-beta-rich plaques in a mouse model, suggesting that, indeed, ROS and amyloid-beta can interact and potentially influence disease progression,” pointed out Moulton.
“As we age, ROS in the brain increases. If in addition there are mutations that disrupt the droplet pathways, then neurons can become sensitive to the accumulation of lipid droplets and this can pave the way to neurodegeneration,” according to Bellen. “Our findings support further investigations into feasible means to reduce the levels of ROS in the brain as a strategy to minimize ROS’s key contribution to neurodegeneration.”
