It was long thought that fat in the brain played no role in neurodegenerative diseases, but Purdue University researchers are challenging that assumption.
The research findings, published in Immunity, show that excess fat in the brain’s resident immune cells, called microglia, impairs their ability to combat disease. This insight opens a path to lipid biology-based neuroimmune therapies that could treat diseases like Alzheimer’s by enhancing microglial function and neuronal health. This work was led by Gaurav Chopra, the James Tarpo Jr. and Margaret Tarpo Professor of Chemistry and (by courtesy) of Computer Science at Purdue.
While most Alzheimer’s drug development targets the primary pathologies of the disease — plaques of a misfolded protein called amyloid beta and tangles of the protein tau — Chopra is focused on the abnormally fat-rich cells surrounding diseased regions of the brain. In earlier work published in Nature, Chopra and collaborators showed that, in the presence of disease, astrocytes — another type of cells that support neurons — release a fatty acid that is toxic to brain cells. Another collaborative work with the University of Pennsylvania, published last year in Nature, also linked mitochondrial dysfunction in neurons with fat deposits in glial cells during aging — a major risk factor for neurodegeneration.
“In our view, directly targeting plaques or tangles will not solve the problem; we need to restore function of immune cells in the brain,” Chopra said. “We’re finding that reducing accumulation of fat in the diseased brain is the key, as accumulated fat makes it harder for the immune system to do its job and maintain balance. By targeting these pathways, we can restore the ability of immune cells like microglia to fight disease and keep the brain in balance, which is what they’re meant to do.”
Chopra’s team worked in collaboration with researchers at Cleveland Clinic led by Dimitrios Davalos, assistant professor of molecular medicine. Chopra is also the director of Merck-Purdue Center and a member of the Purdue Institute for Integrative Neuroscience; the Purdue Institute for Drug Discovery; the Purdue Institute of Inflammation, Immunology and Infectious Disease; and the Regenstrief Center for Healthcare Engineering.
Chopra’s work is part of Purdue’s presidential One Health initiative, which brings together research on human, animal and plant health. His research supports the initiative’s focus on advanced chemistry, where Purdue faculty study complex chemical systems and develop new techniques and applications.
More than 100 years ago, Alois Alzheimer identified abnormalities in the brain of a woman with the disease that now bears his name, including plaques, tangles and cells filled with droplets of fatty compounds called lipids. Until recently, these lipid droplets were dismissed as by-products of disease.
But the links that Chopra and his team have found between neurodegenerative disease and fats in microglia and astrocytes — both types of glial cells that support neurons in the brain — strongly suggest otherwise. Chopra says this research lays the foundation for a “new lipid model of neurodegeneration.” He likes to call these fat accumulations “lipid plaques,” as they don’t resemble spherical droplets.
“It is not the lipid droplets that are pathogenic, but the accumulation of these droplets is bad. We think the composition of lipid molecules that accumulate within brain cells is one of the major drivers of neuroinflammation, leading to different pathologies, such as aging, Alzheimer’s disease and other conditions related to inflammatory insults in the brain. The specific composition of these lipid plaques may define particular brain diseases,” Chopra said.
The Immunity paper focuses on microglia, the “bona fide immune cells of the brain,” which clear out debris, such as misfolded proteins like amyloid beta and tau, by absorbing and breaking them down through a process called phagocytosis. Chopra’s team examined microglia in the presence of amyloid beta and asked a simple question: What happens to microglia when they come into contact with amyloid beta?
Images of brain tissue from people with Alzheimer’s disease showed amyloid beta plaques surrounded by microglia. Microglia located within 10 micrometers of these plaques contained twice as many lipid droplets as those farther away. These lipid droplet-laden microglia closest to the plaques cleared 40% less amyloid beta than ordinary microglia from brains without disease.
In their investigation into why microglia were impaired in Alzheimer’s brains, the team used specialized techniques and found that microglia in contact with plaques and disease-related inflammation produced an excess of free fatty acids. While microglia normally use free fatty acids as an energy source — and some production of these fatty acids is even beneficial — Chopra and his team discovered the microglia closest to amyloid beta plaques convert these free fatty acids to triacylglycerol, a stored form of fat, in such large quantities that they become overloaded and immobilized by their own accumulation. The formation of these lipid droplets depends on age and disease progression, becoming more prominent as Alzheimer’s disease advances.
By tracing the complex series of steps microglia use to convert free fatty acids to triacylglycerol, the research team zeroed in on the final step of this pathway. They found abnormally high levels of an enzyme called DGAT2 catalyzes the final step of converting free fatty acids to triacylglycerol. They expected to see equally high levels of the DGAT2 gene — since the gene must be copied to produce the protein — but that was not the case. The enzyme accumulates because it is not degrading as quickly as it normally would, rather than being overproduced. This accumulation of DGAT2 causes microglia to divert fatty acids into long-term storage and fat accumulation instead of using them for energy or repair.
“We showed that amyloid beta is directly responsible for the fat that forms inside microglia,” Chopra said. “Because of these fatty deposits, microglial cells become dysfunctional — they stop clearing amyloid beta and stop doing their job.”
Chopra said the researchers don’t yet know what causes the DGAT2 enzyme to persist. However, in their search for a remedy, the team tested two molecules: one that inhibits DGAT2’s function and another that promotes its degradation. The degradation of the DGAT2 enzyme was ultimately beneficial to reduce fat in the brains, improve function of microglia and their ability to eat amyloid-beta plaques, and improve markers of neuronal health in Alzheimer’s disease animal models.
“What we’ve seen is that when we target the fat-making enzyme and either remove or degrade it, we restore the microglia’s ability to fight disease and maintain balance in the brain — which is what they’re meant to do,” Chopra said.
“This is an exciting finding that reveals how a toxic protein plaque directly influences how lipids are formed and metabolized by microglial cells in Alzheimer’s brains,” said Priya Prakash, a first co-author of the study. “While most recent work in this area has focused on the genetic basis of the disease, our research paves the way for understanding how lipids and their pathways within the brain’s immune cells can be targeted to restore their function and combat the disease.”
“It’s incredibly exciting to connect fat metabolism to immune dysfunction in Alzheimer’s,” said Palak Manchanda, the other first co-author. “By pinpointing this lipid burden and the DGAT2 switch that drives it, we reveal a completely new therapeutic angle: Restore microglial metabolism and you may restore the brain’s own defense against disease.”
At Purdue, Chopra was joined in the research by Prakash, Manchanda, Kanchan Bisht, Kaushik Sharma, Prageeth R. Wijewardhane, Caitlin Randolph, Matthew Clark, Jonathan Fine, Elizabeth Thayer and Chi Zhang. Their research was produced with support from the U.S. Department of Defense and the National Institutes of Health.