Cure Alzheimer's Fund Cure Alzheimer's Fund

For decades, neurons were the focus of Alzheimer’s research. After all, they die off in large numbers over the course of the disease and are considered the primary cells for memory and other cognitive brain activity. However, when large-scale genetic sequencing of Alzheimer’s patients became possible, the field discovered that the genetics of neurons are not common risk factors for most cases of Alzheimer’s.

Of the common genes with variants that affect risk of sporadic Alzheimer’s disease, more than half are made by microglia, astrocytes and peripheral myeloid cells—not neurons. These cells are the primary immune cells of the central nervous system, and they continuously monitor the brain, quickly responding to pathological changes. They play a crucial role in maintaining brain homeostasis by isolating and clearing out cell debris, pathogens, and cellular byproducts, including amyloid beta plaques. However, under certain conditions, these immune cells can start to malfunction, even degrading healthy synapses and neurons. This is thought to contribute to the neurodegeneration and cognitive decline observed in Alzheimer’s disease.

Neuroinflammation has long been recognized as a hallmark of Alzheimer’s disease, dating back to Dr. Alois Alzheimer’s observations of reactive glial cells in the brain. Modern research suggests that this inflammatory response plays a more active role in disease progression than previously thought. The researchers within the neuroimmune consortium already have identified several genes in microglia important for the development of Alzheimer’s-related pathologies, and demonstrated how these genetic changes can influence peripheral signaling, such as cytokine and hormone responses. Now, the consortium is investigating how inflammation outside the brain may directly impact Alzheimer’s pathology. This bidirectional communication between the brain and the body is crucial for maintaining normal brain function and, when disrupted, may contribute to both the onset and progression of Alzheimer’s disease.

The consortium includes experienced investigators with a track record of collaboration and highly complementary expertise across methods, species, cell types, and in brain and peripheral systems.

NEUROIMMUNE CONSORTIUM: CURRENTLY FUNDED RESEARCHERS

Beth Stevens, Ph.D., Boston Children’s Hospital; Chair of the CureAlz Neuroimmune Consortium

Mathew Blurton-Jones, Ph.D., University of California, Irvine

Christopher Glass, M.D., Ph.D., University of California, San Diego

Shane Liddelow, Ph.D., New York University Langone Medical Center

Martine Therrien, Ph.D., University of California, Davis

Read The Neuroimmune System And Alzheimer’s Disease Brochure here

 

CURRENTLY FUNDED PROJECTS

Effects of peripheral inflammation on myeloid cell function in Alzheimer’s Disease: Beth Stevens, Ph.D., $344,085

  • Brain border-associated macrophages (BAMs) are a unique type of immune cell that sit around the brain’s borders, near blood vessels and membranes. Unlike microglia, BAMs monitor both the brain and the body. Research suggests that BAMs play a role in amyloid buildup in Alzheimer’s disease. The Steven’s lab previously found that as BAMs age, they become more inflammatory and less effective at clearing debris or pathogens. Now, they will investigate how inflammation outside the brain impacts BAMs and whether dysfunctional BAMs contribute to Alzheimer’s. They will explore (1) how inflammation affects BAM numbers and their ability to clear amyloid in a mouse model, (2) which molecules and pathways are altered by inflammation at the brain borders, and (3) potential molecules involved in neuroimmune interactions in human Alzheimer’s cases.

Mechanisms mediating microglia sensing of peripheral inflammation: Christopher Glass, M.D., Ph.D., $287,500

  • This project will explore how immune cells in the brain, particularly microglia, respond to peripheral inflammation. The research team will focus on TLR4, a protein made by microglia, that initiates inflammation and may play a role in Alzheimer’s disease. Their research will map microglia activation in response to peripheral inflammation, explore the necessity of TLR4 for this process, and test whether targeting peripheral immune cells can prevent brain inflammation.

Examining the impact of peripherally derived human macrophages in AD Pathogenesis: Mathew Blurton-Jones, Ph.D., $287,493

  • Immune cells from the blood, known as monocyte-derived macrophages (MDMs), might contribute to Alzheimer’s disease by triggering brain inflammation and amyloid plaque buildup. Using an innovative mouse model that includes human immune cells, the researchers will investigate how MDMs and microglia respond to inflammation and amyloid plaques and if MDMs migrate into the brain during Alzheimer’s disease. They are also developing methods to determine if MDMs are more prevalent in the brains of Alzheimer’s patients than in healthy individuals.

Astrocyte inflammatory contributions to Alzheimer’s disease: Shane Liddelow, Ph.D., $287,500

  • Brain cells that support normal brain function known as astrocytes may contribute to the effects of peripheral inflammation on the brain. Scientists previously identified a type of astrocyte that reacts to an immune protein called interferon (IFN). These cells, located near the brain’s borders, potentially transmit immune signals from the body to the brain. Funded researchers will explore whether these IFN-reactive astrocytes protect the brain under normal conditions and how amyloid plaques may disrupt their function.

Impact of AD polygenic risk score on microglial response to peripheral inflammation: Martine Therrien, Ph.D., $285,850.90

  • While previous studies examined how individual gene variants affect microglia, this project will investigate the combined effect of multiple risk genes. The Polygenic Risk Score (PRS) represents the cumulative influence of multiple genes on a person’s risk of developing a disease. By transplanting human microglia with different PRS scores and APOE variants (E2, E3, E4) into mice, the lab will study how these cells react to inflammation and how genetic variants impact microglia activity in Alzheimer’s disease.

PREVIOUSLY FUNDED PROJECTS

Understanding the consequences of noncoding AD risk alleles on microglia function: Beth Stevens, Ph.D.; $600,000

  • Alzheimer’s disease is a growing public health challenge, and current treatments offer little help in slowing its progression. Research shows that the brain’s immune cells, microglia, play a key role in Alzheimer’s disease, with many genetic risk factors for late-onset Alzheimer’s disease being specific to these cells. However, scientists don’t fully understand how these genetic mutations affect microglial function. This project will profile how microglia change their behavior when genetic risk factors are present and how the resulting changes affect disease progression.

Leveraging enhancer landscapes to decode AD risk alleles in microglia: Christopher Glass, M.D., Ph.D.; $500,000

  • Many of the DNA changes linked to Alzheimer’s disease occur in regions that don’t make proteins. Once thought to be junk DNA, these regions serve an important function by controlling when genes turn on. This project will explore how these noncoding regions of DNA influence Alzheimer’s risk by studying their effects on microglia, the brain’s immune cells. Researchers will focus on specific noncoding regions called enhancers near the BIN1 and MS4A genes, which are known to increase the risk of Alzheimer’s disease.

Assessing the links between the Ms4a risk genes, microglia, and Alzheimer’s disease: Sandeep Robert Datta, M.D., Ph.D.; $1,000,000 (cumulative funding for two grants)

  • Alzheimer’s disease causes memory loss, confusion, and difficulty with daily tasks as it progresses. While neurons, the brain cells responsible for processing information, are damaged in Alzheimer’s, recent research suggests that another type of brain cell, called glia, influence the onset and progression of the disease. Scientists are focusing on a set of genes called MS4As, which seem to particularly affect microglia, to understand how the genes influence the normal function of microglia and the function of microglia during Alzheimer’s disease.

Examining the role of human microglia in the transition between parenchymal and vascular beta amyloid pathology: Mathew Blurton-Jones, Ph.D.; $500,000

  • Amyloid beta builds up in Alzheimer’s disease either as plaques in brain tissue or within the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Over 80% of Alzheimer’s patients are affected by CAA, and it leads to faster cognitive decline and earlier death. Because microglia play a role in where amyloid beta is deposited, this study will explore how TREM2, a gene that affects microglial behavior, influences amyloid buildup, microglia function, and the progression of AD.

Biomarker Tool Development: Jacob Hooker, Ph.D.; $287,500

  • This grant will enable researchers to transform findings from the Neuroimmune Consortium into PET imaging biomarkers that detect specific proteins associated with brain inflammation, offering a powerful tool for earlier and more precise diagnosis.

Investigation of AD risk alleles in astrocytes—focus on cholesterol transport and microglia interactions: Shane Liddelow, Ph.D.; $615,000

  • This project will explore how changes in the clusterin (CLU) and APOE genes contribute to brain inflammation in Alzheimer’s disease. Both genes produce proteins that help astrocytes, which are brain cells that support neurons, transport cholesterol to other brain cells. In Alzheimer’s disease, microglia become overactive and trigger astrocytes to release a toxic fat, leading to neuron death. Researchers will investigate how different versions of the CLU gene, along with variations of APOE, affect this process.

Discovery and development of chemical probes to elucidate MS4A protein function: Jacob Hooker, Ph.D.; $200,000

  • Currently, there are gaps in our understanding of how neuroimmunity contributes to classic AD pathology. These gaps are partly due to a lack of basic tools to trace what is happening in the brain. While blood and spinal fluid tests can show changes in protein levels, they don’t reveal where in the brain these changes occur. Imaging can provide this insight but requires finding specific proteins linked to neuroimmune cells and molecules that can highlight them in brain scans. Researchers will use advanced chemical screening methods to develop these markers, which could eventually help detect brain immune activity through PET scans. Initial efforts will focus on MS4A, which may influence Alzheimer’s disease risk.

Microglial heterogeneity and transcriptional state changes in Alzheimer’s Disease: Beth Stevens, Ph.D.; $598,039

  • The brain’s immune cells, called microglia, play a key role in the development of late-onset AD. These cells normally keep the brain healthy by removing toxic proteins and debris, but in Alzheimer’s, they can trigger inflammation and destroy important brain connections. To understand microglia’s role in Alzheimer’s disease, researchers will study individual brain cells from donated tissue and use advanced tools to map out the cellular changes in both AD and normal aging. This project will also examine how microglia interact with other brain cells and explore how blocking certain inflammatory pathways might prevent brain damage.

Interpretation of noncoding risk alleles for AD: Christopher Glass, M.D., Ph.D.; $500,000

  • Genetic studies have found dozens of DNA changes linked to Alzheimer’s disease risk. Most of these changes don’t occur in the parts of DNA that contain the instructions for building proteins, making it harder to figure out their role in disease risk. This study will explore whether these “noncoding” DNA changes affect the production of specific proteins in brain cells like neurons and microglia. Interestingly, many of these changes seem to influence the proteins made by microglia, suggesting that microglia play a key role in Alzheimer’s disease development.

Neurotoxic reactive astrocytes in Alzheimer’s disease: Shane Liddelow, Ph.D.; $500,000

  • When we think of the brain, neurons are the primary cells that come to mind because they orchestrate thoughts, memories, and movement. However, the brain also contains glial cells that outnumber neurons two to one. Recent studies have linked many Alzheimer’s risk genes to glial cells. Astrocytes, a type of glial cell, help neurons by delivering nutrients and supporting their connections. However, in Alzheimer’s disease, astrocytes turn toxic, releasing substances that harm neurons. In fact, research has shown that these toxic astrocytes gather around dying neurons in Alzheimer’s disease. To learn more, scientists will use advanced single-cell sequencing technology to explore how astrocytes switch from beneficial allies to neurotoxic players, contributing to the progression of Alzheimer’s disease.

Neuroimmune Molecular Imaging: Redefining the Landscape of Opportunities in Alzheimer’s Disease: Jacob Hooker, Ph.D.; $350,000

  • Studies comparing the genetics of people with Alzheimer’s disease to healthy individuals have found that genes involved in regulating the immune system increase the risk for brain degeneration. Recent evidence shows that problems with the brain’s immune system, specifically microglial cells, play a significant role in the development and progression of the disease. However, scientists struggle to image these immune cells in the brains of living patients. This project will work to develop a PET scan tool that can detect changes in microglial activity in the living brain. The team will start by creating a PET radiotracer for the molecule SHIP1, which is involved in microglial activation.

NIC PUBLISHED PAPERS

  1. Chadarevian, J. P., Hasselmann, J., Lahian, A., Capocchi, J. K., Escobar, A., Lim, T. E., Le, L., Tu, C., Nguyen, J., Kiani Shabestari, S., Carlen-Jones, W., Gandhi, S., Bu, G., Hume, D. A., Pridans, C., Wszolek, Z. K., Spitale, R. C., Davtyan, H., & Blurton-Jones, M. Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy. Neuron, August, 21, 2024.
  2. Han, C. Z., Li, R. Z., Hansen, E., Trescott, S., Fixsen, B. R., Nguyen, C. T., Mora, C. M., Spann, N. J., Bennett, H. R., Poirion, O., Buchanan, J., Warden, A. S., Xia, B., Schlachetzki, J. C. M., Pasillas, M. P., Preissl, S., Wang, A., O’Connor, C., Shriram, S., Kim, R., Schafer, D., Ramierz, G., Challacombe, J., Anavim, S. A., Johnson, A., Gupta, M., Glass, I. A., Birth Defects Research Laboratory, Levy, M. L., Ben Haim, S., Gonda, D. D., Laurent, L., Hughes, J. F., Page, D. C., Blurton-Jones, M., Glass, C. K., Coufal, N. G. Human microglia maturation is underpinned by specific gene regulatory networks. Immunity, September 12, 2023.
  3. Frazel, P. W., Labib, D., Fisher, T., Brosh, R., Pirjanian, N., Marchildon, A., Boeke, J. D., Fossati, V., & Liddelow, S. A. Longitudinal scRNA-seq analysis in mouse and human informs optimization of rapid mouse astrocyte differentiation protocols. Nature neuroscience, September 11, 2023.
  4. Fixsen, B. R., Han, C. Z., Zhou, Y., Spann, N. J., Saisan, P., Shen, Z., Balak, C., Sakai, M., Cobo, I., Holtman, I. R., Warden, A. S., Ramirez, G., Collier, J. G., Pasillas, M. P., Yu, M., Hu, R., Li, B., Belhocine, S., Gosselin, D., Coufal, N. G., Ren, B., & Glass, C. K. SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity. Nature immunology, June 15, 2023.
  5. Castranio, E. L., Hasel, P., Haure-Mirande, J. V., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., Liddelow, S. A., & Ehrlich, M. E. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, November 30, 2022.
  6. Dolan, M. J., Therrien, M., Jereb, S., Kamath, T., Gazestani, V., Atkeson, T., Marsh, S. E., Goeva, A., Lojek, N. M., Murphy, S., White, C. M., Joung, J., Liu, B., Limone, F., Eggan, K., Hacohen, N., Bernstein, B. E., Glass, C. K., Leinonen, V., Blurton-Jones, M., Zhang, F., Epstein, C. B., Macosko, E. V., & Stevens, B. Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro. Nature immunology, July 27, 2023.
  7. Bartolo, N. D., Mortimer, N., Manter, M. A., Sanchez, N., Riley, M., O’Malley, T. T., & Hooker, J. M.Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer’s Disease, ACS Chemical Neuroscience, December 6, 2022.
  8. Titus, H. E., Xu, H., Robinson, A. P., Patel, P. A., Chen, Y., Fantini, D., Eaton, V., Karl, M., Garrison, E. D., Rose, I. V. L., Chiang, M. Y., Podojil, J. R., Balabanov, R., Liddelow, S. A., Miller, R. H., Popko, B., & Miller, S. D. Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis. Glia, July 9, 2022.
  9. Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M. H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., Mancusi, R., Yalçın, B., Taylor, K. R., Acosta-Alvarez, L., Malacon, K., Keough, M. B., Ni, L., Woo, P. J., Contreras-Esquivel, D., Toland, A. M. S., Gehlhausen, J. R., Klein, J., Takahashi, T., Silva, J., Israelow, B., Lucas, C., Mao, T., Pena-Hernandez, M. A., Tabachnikova, A., Homer, R. J., Tabacof, L., Tosto-Mancuso, J., Breyman, E., Kontorovich, A., McCarthy, D., Quezado, M., Vogel, H., Hefti, M. M., Perl, D. P., Liddelow, S., Folkerth, R., Putrini, Da., Nath, A., Iwasaki, A., & Monje, M. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell, July 7, 2022.
  10. Kiani Shabestari, S., Morabito, S., Danhash, E. P., McQuade, A., Sanchez, J. R., Miyoshi, E., Chadarevian, J. P., Claes, C., Coburn, M. A., Hasselmann, J., Hidalgo, J., Tran, K. N., Martini, A. C., Chang Rothermich, W., Pascual, J., Head, E., Hume, D. A., Pridans, C., Davtyan, H., Swarup, V., & Blurton-Jones, M. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice. Cell reports, June 14, 2022.
  11. Labib, D., Wang, Z., Prakash, P., Zimmer, M., Smith, M. D., Frazel, P. W., Barbar, L., Sapar, M. L., Calabresi, P. A., Peng, J., Liddelow, S. A., & Fossati, V. (2022). Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models. Frontiers in molecular neuroscience, May 3, 2022.
  12. Kleffman, K., Levinson, G., Rose, I. V. L., Blumenberg, L. M., Shadaloey, S. A. A., Dhabaria, A., Wong, E., Galán-Echevarría, F., Karz, A., Argibay, D., Von Itter, R., Floristán, A., Baptiste, G., Eskow, N. M., Tranos, J. A., Chen, J., Vega Y Saenz de Miera, E. C., Call, M., Rogers, R., Jour, G., Wadghiri, Y. Z., Osman, I., Li, Y., Mathews, P., DeMattos, R., Ueberheide, B., Ruggles, K. V., Liddelow, S. A., Schneider, R. J., & Hernando, E. Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis. Cancer discovery, May 2, 2022.
  13. Sadick, J. S., O’Dea, M. R., Hasel, P., Dykstra, T., Faustin, A., & Liddelow, S. A. Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease. Neuron, April 4, 2022.
  14. Wareham, L. K., Liddelow, S. A., Temple, S., Benowitz, L. I., Di Polo, A., Wellington, C., Goldberg, J. L., He, Z., Duan, X., Bu, G., Davis, A. A., Shekhar, K., Torre, A., Chan, D. C., Canto-Soler, M. V., Flanagan, J. G., Subramanian, P., Rossi, S., Brunner, T., Bovenkamp, D. E., & Calkins, D. J. Solving neurodegeneration: common mechanisms and strategies for new treatments. Molecular neurodegeneration, March 21, 2022.
  15. Marsh, S. E., Walker, A. J., Kamath, T., Dissing-Olesen, L., Hammond, T. R., de Soysa, T. Y., Young, A. M. H., Murphy, S., Abdulraouf, A., Nadaf, N., Dufort, C., Walker, A. C., Lucca, L. E., Kozareva, V., Vanderburg, C., Hong, S., Bulstrode, H., Hutchinson, P. J., Gaffney, D. J., Hafler, D. A., Franklin, R. J. M., Macosko, E. Z., & Stevens, B. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nature neuroscience, March 8, 2022.
  16. Bandler, R. C., Vitali, I., Delgado, R. N., Ho, M. C., Dvoretskova, E., Ibarra Molinas, J. S., Frazel, P. W., Mohammadkhani, M., Machold, R., Maedler, S., Liddelow, S. A., Nowakowski, T. J., Fishell, G., & Mayer, C. (2022). Single-cell delineation of lineage and genetic identity in the mouse brain. Nature, December 15, 2021.
  17. Guttenplan, K. A., Weigel, M. K., Prakash, P., Wijewardhane, P. R., Hasel, P., Rufen-Blanchette, U., Münch, A. E., Blum, J. A., Fine, J., Neal, M. C., Bruce, K. D., Gitler, A. D., Chopra, G., Liddelow, S. A., & Barres, B. A. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature, October 6, 2021.
    1. To learn more about this paper, visit Identified: An Elusive Toxin that Damages Neurons
  18. Hasel, P., Rose, I. V. L., Sadick, J. S., Kim, R. D., & Liddelow, S. A. (2021). Neuroinflammatory astrocyte subtypes in the mouse brain. Nature neuroscience, August 19, 2021.
  19. Barbar, L., Jain, T., Zimmer, M., Kruglikov, I., Sadick, J. S., Wang, M., Kalpana, K., Rose, I. V. L., Burstein, S. R., Rusielewicz, T., Nijsure, M., Guttenplan, K. A., di Domenico, A., Croft, G., Zhang, B., Nobuta, H., Hébert, J. M., Liddelow, S. A., & Fossati, V. CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes. Neuron, August 5, 2021.
  20. Sadick, J. S., Crawford, L. A., Cramer, H. C., 3rd, Franck, C., Liddelow, S. A., & Darling, E. M. Generating Cell Type-Specific Protein Signatures from Non-symptomatic and Diseased Tissues. Annals of biomedical engineering, August 1, 2021.
  21. Prakash, P., Jethava, K. P., Korte, N., Izquierdo, P., Favuzzi, E., Rose, I. V. L., Guttenplan, K. A., Manchanda, P., Dutta, S., Rochet, J. C., Fishell, G., Liddelow, S. A., Attwell, D., & Chopra, G. Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time.Chemical science, July 21, 2021.
  22. Guttenplan, K. A., Stafford, B. K., El-Danaf, R. N., Adler, D. I., Münch, A. E., Weigel, M. K., Huberman, A. D., & Liddelow, S. A. Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury. Cell reports, May 3, 2021.
  23. Nott, A., Schlachetzki, J. C. M., Fixsen, B. R., & Glass, C. K. Nuclei isolation of multiple brain cell types for omics interrogation. Nature protocols, March 18, 2021.
  24. Liddelow, S. A., Marsh, S. E., & Stevens, B. Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Trends in immunology, August 17, 2020.
  25. Sadick, J. S., Crawford, L. A., Cramer, H. C., 3rd, Franck, C., Liddelow, S. A., & Darling, E. M. Generating Cell Type-Specific Protein Signatures from Non-symptomatic and Diseased Tissues. Annals of biomedical engineering, August 1, 2020.
  26. Guttenplan, K. A., Weigel, M. K., Adler, D. I., Couthouis, J., Liddelow, S. A., Gitler, A. D., & Barres, B. A. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nature communications, July 27, 2020.
  27. Hammond, T. R., Marsh, S. E., & Stevens, B. Immune Signaling in Neurodegeneration.Immunity, April 16, 2020.
  28. Nott, A., Holtman, I. R., Coufal, N. G., Schlachetzki, J. C. M., Yu, M., Hu, R., Han, C. Z., Pena, M., Xiao, J., Wu, Y., Keulen, Z., Pasillas, M. P., O’Connor, C., Nickl, C. K., Schafer, S. T., Shen, Z., Rissman, R. A., Brewer, J. B., Gosselin, D., Gonda, D. D., Levy, M. L., Rosenfeld, M. G., McVicker, G., Gage, F. H., Ren, B., & Glass, C. K. Brain cell type-specific enhancer-promoter interactome maps and disease–risk association. Science, February 18, 2020.

Consortia