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Principal Investigator: Hongkuan Fan
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $620,701
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Vascular dysfunction, such as decreases in cerebral blood flow (CBF) and disruption of the blood brain barrier
(BBB) are early symptoms of Alzheimer’s disease (AD) and could contribute to AD onset and progression. In the
brain, specialized cells called pericytes are integral to proper vascular function, as they play a major role in
regulating CBF and maintaining BBB integrity. However, the processes that govern pericyte dysfunction and the
role of pericytes in decreases of CBF in AD development have not been fully elucidated. Our previous studies
have demonstrated that increases in the transcription factor Fli-1 are associated with pericyte dysfunction and
viability via up-regulation of caspase-1 expression. Our preliminary data demonstrated that Fli-1 levels were
higher in the hippocampus and superior temporal gyrus regions of brain tissue from AD patients compared to
controls. Pericytes undergo apoptosis in the hippocampus of AD patients, and pericyte Fli-1 levels were
increased in AD patients. In addition, TNF and aggregated amyloid- induced Fli-1 expression in cultured
human brain pericytes. Furthermore, amyloid- induced pericyte apoptosis, as evidenced by decreased pericyte
viability, increased TUNEL positive cells, and increased expression of apoptosis marker caspase-3. Knockdown
of Fli-1 with antisense oligonucleotide Gapmers suppressed amyloid--induced pericyte death, apoptosis, and
caspase-3 levels. Thus, increased Fli-1 levels in AD patients may lead to pericyte loss. To determine the cause-
effect relationship between increased Fli-1 and AD development, we conducted studies in the 5xFAD mouse
model. Fli-1 levels were higher in the hippocampus in 5xFAD mice and corresponded with spatial learning and
memory impairment in Novel Object Recognition and Morris Water Maze tests. Injection of Fli-1 Gapmer into the
hippocampus significantly decreased Fli-1 and inflammatory mediator levels, mitigated pericye loss and vascular
leakage, suppressed adhesion molecule levels, reduced A deposition, and ameliorated spatial learning and
memory impairment. These data provide the first evidence that increased Fli-1 levels contribute to AD
development. We hypothesize that the transcription factor Fli-1 elevation in Alzheimer's disease leads to
pericyte dysfunction and brain hypoperfusion. Three specific aims are proposed to address this hypothesis:
Aim 1: Determine how Fli-1 regulates pericyte and neurovascular cell dysfunction in a mouse AD model. Aim 2:
Elucidate the mechanisms by which pericyte dysfunction results in brain hypoperfusion and cognitive impairment
in a mouse AD model. Aim 3: Test the therapeutic potential of intrathecal administration of Fli-1 Gapmers in
mouse AD models. The successful completion of the proposed studies will result in a better understanding of
the role of Fli-1 in regulating pericyte dysfunction in AD and the development of a novel treatment strategy for
AD.
Terms: <AD dementia><AD model><Address><Adhesion Molecule><Adventitial Cell><Age Months><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Ammon Horn><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animals><Antisense Agent><Antisense Oligonucleotides><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 1><Apoptosis-Related Cysteine Protease Caspase 3><Astrocytes><Astrocytus><Astroglia><Aβ><BBB disruption><Blood - brain barrier anatomy><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Vessels><Blood brain barrier dysfunction><Blood capillaries><Blood monocyte><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><Brain region><CASP-1><CASP-3><CASP1><CASP1 gene><CASP3><CASP3 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><Caspase-1><Caspase-1 Gene><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cells><Cerebral vascular pericyte><Cerebrovascular Circulation><Cessation of life><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Cytometry><Data><Death><Degenerative Neurologic Disorders><Deposit><Deposition><Development><Disease Progression><Disturbance in cognition><Dysfunction><ELISA><ERGB Transcription Factor><EWSR2><Encephalon><Endothelial Cells><Enzyme-Linked Immunosorbent Assay><Ewing Sarcoma Breakpoint Region 2><Extravasation><FLI1><FLI1 Protein><FLI1 Transcription Factor><FLI1 gene><Fli-1 proto-oncogene, ETS transcription factor><Friend Leukemia Virus Integration 1 Protein><Friend Leukemia Virus Integration 1 Transcription Factor><Friend leukemia virus integration 1><Functional disorder><Goals><Hemato-Encephalic Barrier><Hippocampus><Histologic Technics><Histologic Techniques><Histological Technics><Histological Techniques><Hortega cell><Human><ICE Protease><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1BC><IL-1b Converting Enzyme><IL1B-Convertase><IL1BC><IL1BCE><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Impaired cognition><Impairment><In Situ Nick-End Labeling><Infiltration><Inflammation Mediators><Inflammatory><Injections><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Intrathecal Injections><Knock-out><Knockout><Leakage><Learning><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Marrow Neutrophil><Marrow monocyte><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory><Memory Deficit><Memory impairment><Mice><Mice Mammals><Microglia><Modern Man><Murine><Mus><Mφ><NMR Imaging><NMR Tomography><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nuclear Magnetic Resonance Imaging><Onset of illness><PARP Cleavage Protease><PARP Cleavage Protease Gene><Pericapillary Cell><Pericytes><Perivascular Cell><Physiopathology><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Primary Senile Degenerative Dementia><Process><Programmed Cell Death><Proteins><Resolution><Role><Rouget Cells><SCA-1><SCA-1 Gene><SIC-1><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><Spillage><Superior temporal gyrus><Symptoms><TUNEL><Testing><Tissues><Up-Regulation><Upregulation><Vascular Diseases><Vascular Disorder><Yama><Yama protein><Zeugmatography><a beta peptide><abeta><abeta accumulation><abeta aggregation><alzheimer model><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><antisense oligo><arterial spin labeling><arterial spin tagging><astrocytic glia><aβ accumulation><aβ aggregation><beta amyloid fibril><blood flow in brain><blood vessel disorder><blood-brain barrier disruption><bloodbrain barrier><bloodbrain barrier disruption><brain blood circulation><brain blood flow><brain capillary><brain pericytes><brain perivascular cell><brain tissue><brain vascular pericyte><capillary><caspase-3><cell adhesion protein><cerebral blood flow><cerebral capillary><cerebral circulation><cerebral pericyte><cerebrocirculation><cerebrovascular amyloid><cerebrovascular blood flow><cerebrovascular pericyte><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><compare to control><comparison control><cysteine protease P32><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><disease onset><disorder onset><enzyme linked immunoassay><gitter cell><hippocampal><hypoperfusion><imaging><in vivo><inflammatory mediator><knock-down><knockdown><memory dysfunction><mesoglia><microglial cell><microgliocyte><monocyte><morris water maze><morris watermaze><mouse model><murine model><neural inflammation><neuro-vascular><neuro-vascular unit><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurovascular><neurovascular unit><neutrophil><non-invasive imaging><noninvasive imaging><novel><object recognition><pathophysiology><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><perivascular glial cell><primary degenerative dementia><resolutions><response><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><terminal nick end labeling><therapeutic evaluation><therapeutic testing><treatment strategy><vascular><vascular dysfunction><vasculopathy>