Jaime Grutzendler, MD
Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience; Vice-Chair for Research, Neurology; Director, Center for Experimental Neuroimaging
Research & Publications
Biography
News
Research Summary
The dynamics and logic of neuroglial interactions in neurodegenerative pathologies
The overall goal of our laboratory is to uncover rules that govern the complex interactions between all brain cell types in their unperturbed in vivo microenvironment and to determine how these dynamic cell-cell interactions are disrupted in a variety of disease states. We utilize high-resolution cellular imaging in vivo and fixed tissues of single cells and small clusters of interacting cells combined with novel optical sensors of cellular physiology, optogenetics, chemogenetics, genome editing techniques and methods that we develop for improving the capacity to visualize and manipulate individual cells in their native environment. Our approach tends to be exploratory and hypothesis generating and thus, our results can take us in different directions such that projects in the lab can have a neuronal, glial or vascular focus. Finally, discoveries derived from these investigative strategies inspire our translational neuroscience program aimed at neurodegenerative conditions.
Extensive Research Description
- Cellular and molecular mechanisms of neurodegeneration: Neurodegenerative diseases such as Alzheimer’s are the result of complex and multicellular age-related cellular processes that disrupt normal cellular functions and neuroglial interactions. This eventually results in disruption of intercellular communication, loss of synapses and cell death. We are interested in various components of neurodegeneration including: 1) axonal disruption in Alzheimer’s disease; 2) age-related myelin degeneration; 3) neuroprotective roles of glial cells during amyloid deposition; 4) mechanisms of cell death and corpse removal by glial cells; 5) mechanism of disruption of gliovascular interactions.
- Development of methods for intravital imaging and targeted cellular manipulation: In order to obtain a comprehensive understanding of the dynamics of neurodegenerative processes, we develop and implement a variety of methodologies for high-resolution in vivo optical brain imaging and novel methods for cell-specific labeling and manipulation. Examples of techniques that we have developed include: 1) spectral confocal reflectance microscopy (SCoRe) for high-resolution intravital label-free imaging of myelinated axons; 2) Two photon targeted chemical-apoptotic ablation (2Phatal) of cells in vivo to understand the dynamics of glial interactions with dying cells; 3) discovery of small fluorescent molecules for cell specific labeling during intravital imaging.
- Translational neuroscience: we have active efforts at developing neurotherapeutics within the field of neurodegeneration and nervous system injury. One goal is the development of treatments with cellular specificity. We have and ongoing program involving collaboration with chemists for the development of small molecules with unique properties of crossing the blood brain barrier and entering specific neural cell types to delivering therapeutic cargos. In addition, we are exploring the use of novel biologicals (antibodies and antisense oligos). We aim to apply these therapeutic agents in preclinical studies to target some of the pathological features of degeneration (axonal, myelin, microglia and vascular) that we have uncovered.
Coauthors
Research Interests
Alzheimer Disease; Astrocytes; Axons; Blood-Brain Barrier; Capillaries; Cerebrovascular Circulation; Microscopy; Nerve Fibers, Myelinated; Neuronal Plasticity; Regional Blood Flow; Microglia; Neurodegenerative Diseases; Pericytes
Selected Publications
- Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo.Damisah EC, Hill RA, Rai A, Chen F, Rothlin CV, Ghosh S, Grutzendler J. Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo. Science Advances 2020, 6: eaba3239. PMID: 32637606, PMCID: PMC7319765, DOI: 10.1126/sciadv.aba3239.
- Microglia-Mediated Neuroprotection, TREM2, and Alzheimer's Disease: Evidence From Optical Imaging.Condello C, Yuan P, Grutzendler J. Microglia-Mediated Neuroprotection, TREM2, and Alzheimer's Disease: Evidence From Optical Imaging. Biological Psychiatry 2018, 83: 377-387. PMID: 29169609, PMCID: PMC5767550, DOI: 10.1016/j.biopsych.2017.10.007.
- Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain.Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nature Neuroscience 2018, 21: 683-695. PMID: 29556031, PMCID: PMC5920745, DOI: 10.1038/s41593-018-0120-6.
- TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 2016, 90: 724-39. PMID: 27196974, PMCID: PMC4898967, DOI: 10.1016/j.neuron.2016.05.003.
- Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity.Yuan P, Grutzendler J. Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2016, 36: 632-41. PMID: 26758850, PMCID: PMC4710779, DOI: 10.1523/JNEUROSCI.2531-15.2016.
- Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes.Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. Neuron 2015, 87: 95-110. PMID: 26119027, PMCID: PMC4487786, DOI: 10.1016/j.neuron.2015.06.001.
- Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques.Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nature Communications 2015, 6: 6176. PMID: 25630253, PMCID: PMC4311408, DOI: 10.1038/ncomms7176.
- In vivo imaging of oligodendrocytes with sulforhodamine 101.Hill RA, Grutzendler J. In vivo imaging of oligodendrocytes with sulforhodamine 101. Nature Methods 2014, 11: 1081-2. PMID: 25357236, PMCID: PMC4539948, DOI: 10.1038/nmeth.3140.
- Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy.Schain AJ, Hill RA, Grutzendler J. Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy. Nature Medicine 2014, 20: 443-9. PMID: 24681598, PMCID: PMC3981936, DOI: 10.1038/nm.3495.
- Angiophagy prevents early embolus washout but recanalizes microvessels through embolus extravasation.Grutzendler J, Murikinati S, Hiner B, Ji L, Lam CK, Yoo T, Gupta S, Hafler BP, Adelman RA, Yuan P, Rodriguez G. Angiophagy prevents early embolus washout but recanalizes microvessels through embolus extravasation. Science Translational Medicine 2014, 6: 226ra31. PMID: 24598589, DOI: 10.1126/scitranslmed.3006585.
- Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.Whiteus C, Freitas C, Grutzendler J. Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature 2014, 505: 407-11. PMID: 24305053, PMCID: PMC3947100, DOI: 10.1038/nature12821.
- In vivo imaging of cerebral microvascular plasticity from birth to death.Harb R, Whiteus C, Freitas C, Grutzendler J. In vivo imaging of cerebral microvascular plasticity from birth to death. Journal Of Cerebral Blood Flow And Metabolism : Official Journal Of The International Society Of Cerebral Blood Flow And Metabolism 2013, 33: 146-56. PMID: 23093067, PMCID: PMC3597363, DOI: 10.1038/jcbfm.2012.152.
- Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition.Condello C, Schain A, Grutzendler J. Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Scientific Reports 2011, 1: 19. PMID: 22355538, PMCID: PMC3216507, DOI: 10.1038/srep00019.
- CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis.Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2010, 30: 17091-101. PMID: 21159979, PMCID: PMC3077120, DOI: 10.1523/JNEUROSCI.4403-10.2010.
- Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization.Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature 2010, 465: 478-82. PMID: 20505729, PMCID: PMC2879083, DOI: 10.1038/nature09001.
- Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease.Grutzendler J, Helmin K, Tsai J, Gan WB. Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease. Annals Of The New York Academy Of Sciences 2007, 1097: 30-9. PMID: 17413007, DOI: 10.1196/annals.1379.003.
- ATP mediates rapid microglial response to local brain injury in vivo.Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 2005, 8: 752-8. PMID: 15895084, DOI: 10.1038/nn1472.
- Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches.Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nature Neuroscience 2004, 7: 1181-3. PMID: 15475950, DOI: 10.1038/nn1335.
- Long-term dendritic spine stability in the adult cortex.Grutzendler J, Kasthuri N, Gan WB. Long-term dendritic spine stability in the adult cortex. Nature 2002, 420: 812-6. PMID: 12490949, DOI: 10.1038/nature01276.