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Insights into Alzheimer’s disease from single-cell genomic approaches

Abstract

Alzheimer’s disease (AD) is an age-related disease pathologically defined by the deposition of amyloid plaques and neurofibrillary tangles in the brain parenchyma. Single-cell profiling has shown that Alzheimer’s dementia involves the complex interplay of virtually every major brain cell type. Here, we highlight cell-type-specific molecular perturbations in AD. We discuss how genomic information from single cells expands existing paradigms of AD pathogenesis and highlight new opportunities for therapeutic interventions.

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Fig. 1: Overview of central advantages of single-cell approaches for the study of Alzheimer’s disease.
Fig. 2: Shared cellular pathways disturbed in Alzheimer’s disease as revealed by single-cell genomics.
Fig. 3: Single-cell genomics reveal cell-type-specific perturbations in sensing and regulating neural activity in Alzheimer’s disease.
Fig. 4: Molecular programs adopted in Alzheimer’s disease microglia revealed by single-cell genomics.
Fig. 5: Molecular programs adopted in Alzheimer’s disease astrocytes revealed by single-cell genomics.
Fig. 6: Molecular programs adopted in Alzheimer’s disease oligodendroglia revealed by single-cell genomics.
Fig. 7: Emerging methods to interrogate single-cell profiles in Alzheimer’s disease.

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Acknowledgements

We are grateful to H. Mathys, M. Kellis and all members of his laboratory, and all members of the laboratory of L-H.T. for insightful discussions. We thank the following individuals for valuable discussions and helpful feedback on this paper: M. Victor, J. Penney, E. Niederst, L. Akay, D. von Maydell, P. -C. Pao, L. Bozzelli, A. Bubnys, G. Welch, D. -S. Park and J. M. Bonner. L.-H.T. acknowledges National Institutes of Health grants R01AT011460-01 and R37-NS051874-2. We thank the JPB Foundation, the Belfer Neurodegeneration Consortium, the Glenn Foundation for Medical Research, the Cure Alzheimer’s Fund and the Alana Foundation. We gratefully acknowledge generous support from the following individuals and institutions: R. A. Belfer and R. Belfer, the Ko Hahn family, the Carol and Gene Ludwig Family Foundation, the Halis Family Foundation, L. A. Gimpelson, the Dolby family, J. L. Miller and C. D. Miller, D. B. Emmes and the Marc Haas Foundation. All figures were created with BioRender.com.

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M.H.M. and L.-H.T. conceived the original idea and wrote the paper.

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Correspondence to Li-Huei Tsai.

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Murdock, M.H., Tsai, LH. Insights into Alzheimer’s disease from single-cell genomic approaches. Nat Neurosci (2023). https://doi.org/10.1038/s41593-022-01222-2

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