The new research reverses decades of reflection on the role of fat in Alzheimer’s disease

Excess fat in the immune cells of the brain weaken the defenses against Alzheimer’s. Blocking fat storage has restored their ability to combat diseases.

For many years, scientists have estimated that fat in the brain had little connection with neurodegenerative diseases. Researchers at the University of Purdue now test this point of view.

Their study, published in ImmunityDemonstrates that an accumulation of fat in microglia, immune cells in the brain, weakens their ability to combat disease. The discovery points to new therapeutic strategies in lipid biology which could support microglial activity and improve neuronal health under conditions such as Alzheimer. The work was led by Gaurav Chopra, the James Tarpo Jr. and Margaret Tarpo teacher of chemistry and (by courtesy) of computer science in Purdue.

Look beyond plates and tangles

Most Alzheimer’s development treatments are aimed at the main characteristics of the disease: amyloid beta protein plates and tau protein tangles. Chopra, however, draws attention to unusual fat cells found around the damaged areas of the brain.

In previous research published in NatureChopra and her colleagues have shown that astrocytes – cells that provide neurons – eliminate fat acid It becomes toxic to brain cells under disease conditions. Another collaborative study with the University of Pennsylvaniaalso published in Nature The previous year, linked to the mitochondrial dysfunction linked to age in neurons to the accumulation of fat in glial cells, highlighting a key factor of neurodegeneration.

“In our opinion, the targeting directly of plates or tangles will not solve the problem; we must restore the function of immune cells in the brain,” said Chopra. “We note that the reduction in the accumulation of fats in the sick brain is the key, because accumulated fat makes it more difficult for the immune system to do its work and maintain balance.

The Chopra team worked in collaboration with researchers from the Cleveland Clinic led by Dimitrios Davalos, assistant professor of molecular medicine. Chopra is also director of the Merck-Purdue Center and member of the Purdue Institute for Integrative Neuroscience; The Purdue Institute for Drug Discovery; The Purdue Institute of Inflammation, Immunology and Infectious Diseases; and the Regensstrief Center for Healthcare Engineering.

Chopra’s work is part of the One of Purdue presidential initiative, which brings together research on human, animal and vegetable health. His research supports the emphasis on the initiative on advanced chemistry, where Purdue teachers study complex chemical systems and develop new techniques and applications.

Fatty droplets as engines of the disease

More than a century ago, Alois Alzheimer documented unusual characteristics in the brain of a patient with the state later named after him. These included protein plates, tangles and cells filled with lipid droplets. For many years, these lipid deposits have been considered as simple by-products of the disease.

Chopra and her colleagues, however, revealed solid evidence connecting fats in microglia and astrocytes – two types of glial cells that support neurons – to neurodegeneration. Based on these results, Chopra offers a “new lipid model of neurodegeneration”, qualifying these accumulations “lipid plates” because they differ in the shape of typical spherical droplets.

“It is not the lipid droplets that are pathogenic, but the accumulation of these droplets is bad. We believe that the composition of lipid molecules that accumulates in brain cells is one of the main engines of neuroinflammation, leading to different pathologies, such as aging, Alzheimer’s disease, and other conditions linked to inflammatory insults, the specific composition of lipid plaque perhaps in particular in the brain. Said Chopra.

Microglia altered by accumulation of lipids

THE Immunity The paper focuses on microglia, “immune cells in good faith from the brain”, which remove debris, such as poorly folded proteins like the beta amyloid and the tau, by absorbing and decomposing them by a process called phagocytosis. The Chopra team examined Microglia in the presence of the amyloid beta version and asked a simple question: what happens to Microglia when they come into contact with the amyloid beta?

Images of brain tissue from people with Alzheimer’s disease have shown amyloid beta plates surrounded by microglies. The microglia located less than 10 micrometers from these plates contained twice as many lipid droplets than those more distant. These microglies loaded with lipid droplets closest to the plates have eliminated 40% less amyloid beta than the ordinary microglia of the brain without disease.

How fatty acids become trapped

In their survey of the reasons why microglia was altered in Alzheimer’s brain, the team used specialized techniques and found that microglia in contact with plates and inflammation linked to the disease produced excess free fatty acids. While microglies normally use free fatty acids as a source of energy – and a certain production of these fatty acids is even beneficial – Chopra and its team have discovered microglia closest to beta amyloid plates 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 the progression of age and disease, becoming more important as Alzheimer’s disease progresses.

By tracing the complex series of steps that microglia uses to convert free fatty acids to triacylglycérol, the research team focused on the last stage of this track. They found abnormally high levels of an enzyme called DGAT2 catalyzes the last step in converting free fatty acids into triacylglycérol. They expected to see equally high levels of the DGAT2 gene – because the gene must be copied to produce the protein – but that was not the case. The enzyme accumulates because it does not degrade as quickly as it would normally, rather than being overproduced. This accumulation of DGAT2 means that microglia diverts fatty acids in long -term storage and fat accumulation instead of using them for energy or repair.

Restoration of the microglial function

“We have shown that the amyloid beta version is directly responsible for the fat that forms inside microglia,” said Chopra. “Due to these fatty deposits, microglial cells become dysfunctional – they stop cleaning the amyloid beta and stop doing their job.”

Chopra said that researchers do not yet know what causes the DGAT2 enzyme to persist. However, in their search for a remedy, the team tested two molecules: one that inhibits the function of DGAT2 and another which promotes its degradation. The degradation of the DGAT2 enzyme was finally beneficial to reduce fat in the brain, improve the function of microglia and their ability to eat amyloid-bêta plates and improve neural health markers in animal models of Alzheimer’s disease.

“What we have seen is that when we target the fat -making enzyme and delete it or degrades, we remain the capacity of microglia to fight against diseases and maintain balance in the brain – what they are supposed to do,” said Chopra.

“This is an exciting discovery that reveals how a toxic protein plaque directly influences how lipids are formed and metabolized by microglial cells in the brain of Alzheimer,” said Priya Prakash, a first co-author of the study. “While the most recent work in this area has concentrated on the genetic basis of the disease, our research opens the way to understand how lipids and their ways in the immune cells of the brain can be targeted to restore their function and fight the disease.”

“It is incredibly exciting to link fat metabolism to immune dysfunction in Alzheimer’s disease,” said Palak Manchanda, the other first author. “By identifying this lipid charge and the DGAT2 switch which drivers it, we reveal a brand new therapeutic angle: restore microglial metabolism and you can restore the own defense of the brain against the disease.”

References:

“Neurotoxic reactive astrocytes induce cell death via saturated lipids” by Kevin A. Guttenplan, Maya K. Weigel, Priya Prakash, Prageeth R. Wijewardhane, Philip Hasel, Uriel Rufen-Blanchette, Alexandra E. Münch, Jacob A. Blum, Jonathan, Gitler, Gaurav Chopra, Shane A. Liddelow and Ben A. Barres, October 6, 2021, Nature.
DOI: 10.1038/S41586-021-03960-Y

“Microglial dysfunction mediated by lipid drops with amyloid inductids via the Dgat2 enzyme in Alzheimer’s disease by Priya Prakash, Palak Manchanda Rajpoot, Victoria Wendt, Ahad Hossain, Prageth R. Wijewardhane, Caitlin E. Randolph, Yihao Cen, Sarah Nadia Gasmemi, Yihao Chen, Sarah Stanko, Nadia Pasmi, Randolp Axhela Gjojdeshi, Sophie Card, Krupal Pin Jethava, Matthew G. Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A. Thyer, Marlo Nicolas, Ryann Davis, Dhruv Fherikar, Daniela Allende, Richard, Chi Zhang, Dimitri Davalos and Gaurava, 19 May 2025, Dimitri Davalos and Gaurava, 19 May 2025 ,, Dimitri Davalos and Gaurava, 19 May 2025 ,, Dimitri Davalos and Gaurava, 19 May 2025 ,, Dimitri Davalos and Gaurava, 19 me, 19 Immunity.
DOI: 10.1016 / J.IMMUN.2025.04.029

“Mitochondrial dysfunction of the senescent Glia and accumulation of lipids” by China N. Byrns, Alexandra E. Perlegos, Karl N. Miller, Zhecheng Jin, Faith R. Carranza, Palak Manchandra, Connor H. Beveridge, Caitlin E. Randolph, V. Sai Chalvadi, Shirley L. Zhang Annantre R. Saivadi, Shirley L. Zhang, Annantre R. Saivadi, Shirley L. Zhang, Annantre R. FC Bennett, Amita Sehgal, Peter D. Adams, Gaurav Chopra and Nancy M. Bonini, June 5, 2024, Nature.
Two: 10.1038 / S41586-024-07516-8

Financing: American Department of Defense, NIH / National Institute of Neurological Disorders and Stroke, NIH / National Institute of Mental Health, NIH /National Health InstitutesNIH / National Institute of Aging

Never miss a breakthrough: join the Scitechdaily newsletter.