Alzheimer Disease; Astrocytes; Axons; Blood-Brain Barrier; Capillaries; Cerebrovascular Circulation; Microscopy; Nerve Fibers, Myelinated; Neuronal Plasticity; Regional Blood Flow; Microglia; Neurodegenerative Diseases; Pericytes
The dynamics and logic of neuro-glio-vascular interactions in health and diseaseThe overall goal of our laboratory is to uncover rules that govern the complex interactions between all brain cell types in their unperturbed in vivo environment 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 and may be directed towards understanding normal physiology or neuropathology.
Extensive Research Description
- IN VIVO IMAGING:The majority of projects in the laboratory are imaging-oriented. We use a variety of techniques including transcranial in vivo two photon microscopy, high-resolution confocal, spectral confocal reflectance microscopy (SCoRe) and electron microscopy in combination with differential fluorescent cell labeling and genetic/pharmacological manipulations. We aim at developeing novel imaging strategies and methods to better understand the pathophysiology of a variety of neurological disorders.
- "NEURO-GLIO-VASCULAR UNIT" FUNCTION AND PATHOLOGY: Understanding the postnatal development and pathology of neuro-glio-vascualr interactions, neurovascular coupling, tissue oxygenation. Astrocyte physiology.
- MICROVASCULAR PLASTICITY: microvascular recanalization and angioplasticity after cerebral embolic occlusion. We have recently described a new mechanism of microvascular plasticity which leads to vessel recanalization (Angiophagy). We are investigating the molecular control and physiological relevance of this novel mechanism.
- AXONAL AND SYNAPTIC DEGENERATION/REGENERATION: We have recently developed a method for imaging myelinated axons in vivo (Spectral confocal reflectance microscopy SCoRe), which we are currently using to explore questions related to myelin's role in degeneration and regeneration.
- ALZHEIMER"S DISEAESE: understanding the dynamics of neurodegenerative conditions such as Alzheimer's disease. We study the interactions between microglia, neurons and amyloid plaques to understand the sequence of events leading to neural dysfunction in AD.
- 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. Neuron. 2016 May 18;90(4):724-39. 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. J Neurosci. 2016 Jan 13;36(2):632-41. doi: 0.1523/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. 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. Neuron. 2015 Jun 23. pii: S0896-6273
- Microglia constitute a barrier that prevents neurotoxic protofibrillar Aß42 hotspots around plaques. Condello C, Yuan P, Schain A, Grutzendler J. Nature Comms. 2015 Jan 29;6 :6176.
- In vivo imaging of oligodendrocytes using sulforhodamine 101. R. Hill and J. Grutzendler. Nature Methods, 2014. Oct 30;11:1081-1082.
- Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy. Schain A, Hill R, Grutzendler J. Nature Medicine. 2014 Mar 30; Epub 2014 Mar 30.
- Angiophagy prevents early embolus washout but leads to microvascular recanalization through embolus extravasation. Grutzendler J, Murikinati S, Hiner B ,Lam C , Yoo T ,Ji L, Hafler B, Adelman R ,Gupta S, Yuan P, Rodriguez G. Science Translational Medicine. 2014. 6:226-231
- Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period.C. Whiteus, C. Freitas, J. Grutzendler. Nature. 2013, Dec 04 .505, 407–411
- In vivo imaging of cerebral microvascular plasticity from birth to death. Harb R, Whiteus C, Freitas C, Grutzendler J. J Cereb Blood Flow Metab. 2012 Oct 24.
- Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. C. Condello, A. Schain, J. Grutzendler. Scientific Reports. 2011. 1,19. doi:10.1038/srep00019.
- CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-ß phagocytosis. Liu Z, Condello C, Schain A, Harb R, Grutzendler J. J Neurosci. 2010 Dec 15;30(50):17091-101.
- Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J. Nature. 2010 May 27;465(7297):478-82.
- Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer's disease. Grutzendler J, Helmin K, Tsai J, Gan WB. Ann N Y Acad Sci. 2007 Feb;1097:30-9.
- 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. Nat Neurosci. 2005 Jun;8(6):752-8.
- Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Tsai J, Grutzendler J, Duff K, Gan WB. Nat Neurosci. 2004 Nov;7(11):1181-3
- Long-term dendritic spine stability in the adult cortex. Grutzendler J, Kasthuri N, Gan WB. Nature. 2002 Dec 19-26;420(6917):812-6.