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Project

The role of microglia in the pathogenesis of Alzheimer’s Disease

Accumulation of misfolded, aggregated proteins and the associated neuronal cell loss are characteristic hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the deposition of extracellular amyloid β (Aβ)-plaques, intracellular hyperphosphorylated Tau tangles, neuroinflammation, and neuronal loss. The classical dogma of AD describes Aβ as causing factor, which then, by uncharacterized mechanisms, induces Tau hyperphosphorylation and aggregation, and finally leads to neuronal degeneration1–3. Microglia, the resident immune cells of the brain, orchestrate the neuroinflammation in response to the accumulating Aβ plaques and have been hypothesized as an important player AD progression. This hypothesis is further fueled by the observations from recent genome-wide association studies (GWAS)4–6. Many AD risk genes are expressed in microglia7–9. However, the role of inflammation in the pathological cascade of AD is not well understood10–13. In this study, we aim to establish the role of microglia in the pathogenesis of AD. While AD is characterized by Aβ plaques, Tau tangles, and neuronal loss, currently available rodent models do not sufficiently model the AD pathology14–16. Interestingly, iPSC-derived human neurons grafted into amyloid-bearing mice showed that the neurons integrate well, and develop AD-relevant pathologies16,17. Intriguingly these human neurons display Tau pathology and cell death which is not apparent in control mice. It is important to note that these changes are specific to human neurons and not observed in the host mouse neurons16,17. Therefore, this model represents a superior approach to model phenotypes related to AD. In this project, we investigate to what extent neuroinflammation mediated by microglia contribute to pTau and neuronal cell death in the chimeric model of AD. To delineate the role of neuroinflammation in the pathogenesis of AD, we use AppNL-G-F/ Rag2-/- (amyloid mice) which develop amyloid pathology as early as 3 months old, and Apphu/hu/ Rag2-/- (control) mice. We will transplant human stem cell-derived neuronal precursor cells into the brains of immunodeficient AppNL-G-F/ Rag2-/- and Apphu/hu/ Rag2-/-. To study the role of microglia, we will deplete microglia in AppNL-G-F/Rag2-/- mice using PLX3397 treatment. Myeloid lineage cells are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling. Using a selective CSF1R inhibitor like PLX3397, almost all microglia in the brain are depleted in about 21 days18. We will quantify the cell death of the grafted neurons in these models at different time points and perform immunofluorescence analysis. We will mainly focus on necroptosis since the necroptosis pathway is activated in AD brains and correlates well with Braak stages and neurodegeneration3,19. Additionally, we will conduct single nuclei sequencing, as well as bulk sequencing of the grafted neurons. With this approach, we hope to identify differences in neuronal death, morphology, and transcriptional profile of the xenografted cells and the pathology of the mouse brains, which we will explore further. References 1. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). 2. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297, 353–356 (2002). 3. Koper, M. J. et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol. 139, 463–484 (2020). 4. Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019). 5. Bertram, L. et al. Genome-wide Association Analysis Reveals Putative Alzheimer’s Disease Susceptibility Loci in Addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008). 6. Guerreiro, R. et al. TREM2 variants in AD. N. Engl. J. Med. 368, 117–127 (2013). 7. Sala Frigerio, C. et al. The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell Rep. 27, 1293-1306.e6 (2019). 8. Sierksma, A., Escott-Price, V. & De Strooper, B. Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets. Science (80-. ). 370, 61–66 (2020). 9. Sierksma, A. et al. Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology. EMBO Mol. Med. 12, 1–18 (2020). 10. Hansen, D. V, Hanson, J. E. & Sheng, M. Microglia in Alzheimer ’ s disease. J. Cell Biol. 217, 459–472 (2018). 11. Ulland, T. K. & Colonna, M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018). 12. Kepp, K. P. Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease. J. Alzheimer’s Dis. 55, 447–457 (2017). 13. De Strooper, B. & Karran, E. The Cellular Phase of Alzheimer’s Disease. Cell 164, 603–615 (2016). 14. Kuo, Y. M. et al. Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer’s Disease Brains. J. Biol. Chem. 276, 12991–12998 (2001). 15. Maeda, J. et al. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. J. Neurosci. 27, 10957–10968 (2007). 16. Espuny-Camacho, I. et al. Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain. Neuron 93, 1066-1081.e8 (2017). 17. Linaro, D. et al. Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits. Neuron 104, 972-986.e6 (2019). 18. Elmore, M. R. P. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). 19. Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017).

Date:10 Sep 2021 →  Today
Keywords:Alzheimer's Disease, microglia, tau, necroptosis, xenograft, neuroinflammation, neurodegeneration
Disciplines:Neurological and neuromuscular diseases, Cognitive neuroscience
Project type:PhD project