WEST LAFAYETTE, Ind. \u2014 It was long thought that fat in the brain played no role in neurodegenerative diseases, but Purdue University researchers are challenging that assumption.<\/p>\n\n\n\n
The research findings<\/a>, published in Immunity, show that excess fat in the brain\u2019s 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\u2019s 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.<\/p>\n\n\n\n While most Alzheimer\u2019s drug development targets the primary pathologies of the disease \u2014 plaques of a misfolded protein called amyloid beta and tangles of the protein tau \u2014 Chopra is focused on the abnormally fat-rich cells surrounding diseased regions of the brain. In earlier work published in Nature<\/a>, Chopra and collaborators showed that, in the presence of disease, astrocytes \u2014 another type of cells that support neurons \u2014 release a fatty acid that is toxic to brain cells. Another collaborative work with the University of Pennsylvania<\/a>, published last year in Nature<\/a>, also linked mitochondrial dysfunction in neurons with fat deposits in glial cells during aging \u2014 a major risk factor for neurodegeneration.<\/p>\n\n\n\n \u201cIn our view, directly targeting plaques or tangles will not solve the problem; we need to restore function of immune cells in the brain,\u201d Chopra said. \u201cWe\u2019re 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\u2019re meant to do.\u201d<\/p>\n\n\n\n Chopra\u2019s 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.<\/p>\n\n\n\n Chopra\u2019s work is part of Purdue\u2019s presidential One Health initiative, which brings together research on human, animal and plant health. His research supports the initiative\u2019s focus on advanced chemistry, where Purdue faculty study complex chemical systems and develop new techniques and applications.<\/p>\n\n\n\n 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.<\/p>\n\n\n\n But the links that Chopra and his team have found between neurodegenerative disease and fats in microglia and astrocytes \u2014 both types of glial cells that support neurons in the brain \u2014 strongly suggest otherwise. Chopra says this research lays the foundation for a \u201cnew lipid model of neurodegeneration.\u201d He likes to call these fat accumulations \u201clipid plaques,\u201d as they don\u2019t resemble spherical droplets.<\/p>\n\n\n\n \u201cIt 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\u2019s disease and other conditions related to inflammatory insults in the brain. The specific composition of these lipid plaques may define particular brain diseases,\u201d Chopra said.<\/p>\n\n\n\n The Immunity paper focuses on microglia, the \u201cbona fide immune cells of the brain,\u201d 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\u2019s 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?<\/p>\n\n\n\n Images of brain tissue from people with Alzheimer\u2019s 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.<\/p>\n\n\n\n In their investigation into why microglia were impaired in Alzheimer\u2019s 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 \u2014 and some production of these fatty acids is even beneficial \u2014 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\u2019s disease advances.<\/p>\n\n\n\n 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 \u2014 since the gene must be copied to produce the protein \u2014 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.<\/p>\n\n\n\n \u201cWe showed that amyloid beta is directly responsible for the fat that forms inside microglia,\u201d Chopra said. \u201cBecause of these fatty deposits, microglial cells become dysfunctional \u2014 they stop clearing amyloid beta and stop doing their job.\u201d<\/p>\n\n\n\n Chopra said the researchers don\u2019t 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\u2019s 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\u2019s disease animal models.<\/p>\n\n\n\n \u201cWhat we\u2019ve seen is that when we target the fat-making enzyme and either remove or degrade it, we restore the microglia\u2019s ability to fight disease and maintain balance in the brain \u2014 which is what they\u2019re meant to do,\u201d Chopra said.<\/p>\n\n\n\n \u201cThis is an exciting finding that reveals how a toxic protein plaque directly influences how lipids are formed and metabolized by microglial cells in Alzheimer\u2019s brains,\u201d said Priya Prakash, a first co-author of the study. \u201cWhile 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\u2019s immune cells can be targeted to restore their function and combat the disease.\u201d<\/p>\n\n\n\n \u201cIt\u2019s incredibly exciting to connect fat metabolism to immune dysfunction in Alzheimer\u2019s,\u201d said Palak Manchanda, the other first co-author. \u201cBy 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\u2019s own defense against disease.\u201d<\/p>\n\n\n\n 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.<\/p>\n\n\n\n Purdue University is a public research university leading with excellence at scale. Ranked among top 10 public universities in the United States, Purdue discovers, disseminates and deploys knowledge with a quality and at a scale second to none. More than 107,000 students study at Purdue across multiple campuses, locations and modalities, including more than 58,000 at our main campus locations in West Lafayette and Indianapolis. Committed to affordability and accessibility, Purdue\u2019s main campus has frozen tuition 14 years in a row. See how Purdue never stops in the persistent pursuit of the next giant leap \u2014 including its integrated, comprehensive Indianapolis urban expansion; the Mitch Daniels School of Business; Purdue Computes; and the One Health initiative \u2014 at https:\/\/www.purdue.edu\/president\/strategic-initiatives<\/a>.<\/p>\n\n\n\n Amyloid-\u03b2 induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer\u2019s disease<\/em> Neurotoxic reactive astrocytes induce cell death via saturated lipid<\/em> Senescent glia link mitochondrial dysfunction and lipid accumulation<\/em>About Purdue University<\/h2>\n\n\n\n
Papers<\/h2>\n\n\n\n
Immunity
DOI: https:\/\/doi.org\/10.1016\/j.immuni.2025.04.029<\/a><\/p>\n\n\n\n
Nature
DOI: https:\/\/doi.org\/10.1038\/s41586-021-03960-y<\/a><\/p>\n\n\n\n
Nature
DOI: https:\/\/doi.org\/10.1038\/s41586-024-07516-8<\/a><\/p>\n\n\n