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Principal Investigator: Francesca-Fang Liao
Organization: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
Fiscal Year: 2021
Award: $1,967,005
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract
White matter (WM) damage has increasingly been recognized as an important contributing factor to
neurodegeneration and dementia, however, little is known of the specific molecular and cellular events
underlying the pathogenesis. Clinically, chronic hypoperfusion is often associated with WM changes in small
vessel disease. We previously demonstrated that mice deficient in endothelial nitric oxide synthase (eNOS)
spontaneously develop chronic cerebral hypoperfusion in multiple areas that precisely match to the most
vulnerable areas of hypoperfusion in early demented patients, surrounded by elevated ROS and
neuroinflammation, microbleeds, cerebral amyloid angiopathy in middle aged mice, followed by hippocampal
neurodegeneration in older age. Moreover, these mice develop WM changes (e.g., myelin and oligodendrocyte
loss) at middle age, accompanied by marked astrogliosis and selective loss of pyramidal neurons in cortical
layers 2/3 and 5/6. We found upregulated bone morphogenic protein BMP4 in pericytes in these mice at younger
age, preceding myelin loss, and pericytes are the most vulnerable cell type to hypoperfusion among the others
in neurovascular unit. We therefore hypothesize that pericyte degeneration is the earliest pathological event in
WM in eNOS-deficient model, preceding blood-brain-barrier breakdown, astrogliosis, myelin loss and neocortical
neurodegeneration; pericyte-BMP4 is a critical initiating factor to these events. Three Aims are proposed. Aim
1. We will use optical histological approach to image pericytes in whole brain after clearing to determine when
and where pericyte losses occur in eNOS model, and the cell-cell communication in neuro-glial vascular units.
Aim 2. We will profile expressional changes of BMP4 in different cell types using BMP4-CFP reporter mice as
well as validate BMP4 protein upregulation in WM pericytes in human brain cortical samples of a large cohort of
vascular dementia cases. We will also block overactivated BMP4 signaling at early age by Noggin infusion to
CNS and fully characterize gene alteration on microvessels by RNAseq analysis. Positive outcome will identify
novel molecular mechanism and molecules as potential therapeutic targets for WM disease. Aim 3.
Neurophysiological determination of white and gray matter functions in eNOS deficient mice. We will conduct in
vitro electrophysiology (brain slice recording) to detect WM axonal functional abnormalities in corpus callosum
and patch clamping for cortical neuronal abnormalities in intrinsic membrane excitability, action potential
properties and excitatory synaptic circuits in cortical layer 2/3 and 5/6, as well as in vivo electrophysiology-tetrode
spike recording in freely moving mice. Successful completion of these tasks will provide direct evidence for a
causative role and mechanisms of WM and vascular changes in WM and cortical dysfunction and functional loss
in neurodegenerative diseases, a highly under-explored area.
Terms: <AD dementia><Action Potentials><Address><Adventitial Cell><Age><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Amentia><Ammon Horn><Architecture><Area><Arteriosclerotic Dementia><Axon><Axon Terminals><BBB function><BMP4><Blood - brain barrier anatomy><Blood Vessels><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cerebral Amyloid Angiopathy><Cerebral cortex><Chronic><Clinical><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Congophilic Angiopathy><Cornu Ammonis><Corpus Callosum><Corpus Callosums><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dementia><Disturbance in cognition><Dysfunction><ENOS><Electrophysiology><Electrophysiology (science)><Encephalon><Endothelial Nitric Oxide Synthase><Engineering / Architecture><Ensure><Event><Extravasation><Functional disorder><Gene Alteration><Gene Mutation><Health><Hemato-Encephalic Barrier><Hippocampus><Hippocampus (Brain)><Histologic><Histologically><Histology><Human><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impaired cognition><Impairment><In Vitro><Infusion><Infusion procedures><Intracellular Communication and Signaling><Label><Leakage><Mediating><Membrane><Methods><Mice><Mice Mammals><Microvascular Dysfunction><Modeling><Modern Man><Molecular><Murine><Mus><Myelin><NOS3><NOS3 gene><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Neurophysiology / Electrophysiology><Nitric Oxide Synthase 3><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Optics><Outcome><Pathogenesis><Pathologic><Pathology><Patients><Pericapillary Cell><Pericytes><Perivascular Cell><Physiopathology><Play><Presynaptic Nerve Endings><Presynaptic Terminals><Primary Senile Degenerative Dementia><Property><Proteins><Pyramidal neuron><RNA Seq><RNA sequencing><RNAseq><Regulation><Reporter><Role><Rouget Cells><Sampling><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Spillage><Synaptic Boutons><Synaptic Terminals><System><Techniques><Testing><Therapeutic><Tissues><Type III nitric oxide synthase><Up-Regulation><Upregulation><Vascular Cognitive Impairment><Vascular Dementia><White Matter Disease><Work><ages><astrogliosis><base><biological signal transduction><blood-brain barrier function><bloodbrain barrier><bloodbrain barrier function><bone morphogenic protein><cell type><cerebral hypoperfusion><cerebrovascular amyloidosis><cognitive dysfunction><cognitive loss><cohort><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><demented><dementia of the Alzheimer type><electrophysiological><functional loss><gray matter><hippocampal><hippocampal pyramidal neuron><hypoperfusion><imaging><in vivo><membrane structure><microvascular complications><microvascular disease><mid life><mid-life><middle age><middle aged><midlife><mouse model><murine model><neocortical><neural circuit><neural circuitry><neural degeneration><neuro-vascular unit><neurocircuitry><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal circuit><neuronal circuitry><neuronal degeneration><neurophysiological><neurophysiology><neurotransmitter release><neurovascular unit><novel><optical><paracrine><patch clamp><pathophysiology><preservation><prevent><preventing><primary degenerative dementia><senile dementia of the Alzheimer type><small vessel disease><social role><substantia alba><substantia grisea><synaptic circuit><synaptic circuitry><therapeutic target><transcriptome sequencing><vascular><vascular cognition impairment><vascular cognitive decline><vascular cognitive disease><vascular cognitive dysfunction><vascular contributions to cognitive impairment><vascular contributions to dementia><white matter><white matter change><white matter damage>