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Principal Investigator: RICK B MEEKER
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2020
Award: $388,750
Funding agency: National Institute of Neurological Disorders and Stroke
HIV infection of the nervous system results in chronic infection, inflammation and cognitive decline in many
patients with no effective treatments. Inflammation appears early in the disease process and causes
progressive neural damage due, in part, to factors released by activated microglia and macrophages. In
cultured neurons these factors induce intracellular calcium accumulation, cytoskeletal damage and focal
swelling, much like the early Alzheimer disease (AD)pathology, suggesting a common substrate for disease
progression. In gp120 transgenic mice and AD mouse models we recently identified a unique form of Tau
that accumulated in the neuritic swellings. The same Tau accumulated naturally in the hippocampus of
aging and gp120 Tg mice in parallel with p75NTR expression and Iba-1 immunoreactive microglia suggesting
an important link between inflammation, aging and neurodegeneration. In preliminary multielectrode array
(MEA) studies, these early indices of neural damage and Tau accumulation correlated with the appearance
of burst-like activity patterns, increased spike frequencies and a decreased density of neuron
interconnections, all signs of network dysfunction. At the cellular level, hyperresponsiveness contrasted
with the restricted network activity highlighting the need to better understand how changes in neuronal
function translate to network function. Treatment strategies targeted to these early, reversible
manifestations of the disease process have the potential to stabilize cognitive function and perhaps
suppress pathogenesis. We propose a series of experiments that will provide complementary in vitro and in
vivo analyses of the temporal development of network dysfunction in mouse models of HIV-associated
inflammation. In vitro studies of mixed neural cultures from gp120 Tg, Tau overexpressing, p75
neurotrophin receptor deficient and wild type mice will utilize high content recording of neural activity on
4096 electrode culture grids, calcium imaging of primary neurons, morphometry and immunocytochemistry
to examine the contribution of HIV pathology to the development of neural and network dysfunction under
both normal and disease prone conditions. Parallel studies will examine the relative contribution of
microglia as well as HIV Tat protein. Subsequent microwire array recording in vivo to examine hippocampal
mesoscale neural network activity, communication and function in gp120 Tg mice crossed to Tau
overexpressing and p75 deficient mice will begin to reveal how network behavior is modified as pathology
progresses. Mice with confirmed network dysfunction will be evaluated for cognitive function which will be
correlated with MRI/PET studies of synaptic loss and microglial activation with the SV2A synaptic vesicle
protein probe 11C-UCB-J and the mitochondrial TSPO probe 18F-PBR111, respectively. We believe this
integrated approach will identify and characterize HIV-associated network dysfunction and open new
avenues for disease modifying therapeutic intervention.
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biologic function><Neurophysiology / Electrophysiology><Neurotropin Receptor p75><Nuclear Magnetic Resonance Imaging><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathogenesis><Pathogenicity><Pathology><Patients><Pattern><Pb element><Peptides><Phenotype><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Process><Property><Proteins><Rad.-PET><Series><Swelling><Synapses><Synaptic><Synaptic Vesicles><Therapeutic Intervention><Transgenes><Transgenic Mice><Transgenic Organisms><Translating><Translations><Virus-HIV><Wild Type Mouse><Zeugmatography><abnormally aggregated tau protein><aged hippocampus><aging hippocampus><chronic infection><cognitive defects><cognitive disease><cognitive disorder><cognitive dysfunction><cognitive function><cognitive loss><cognitive syndrome><dementia of the Alzheimer type><density><design><designing><developmental><early detection><early therapy><effective therapy><effective treatment><electrophysiological><experiment><experimental research><experimental study><filamentous tau inclusion><gitter cell><gp120><gp120 ENV Glycoprotein><gp120(HIV)><gp75 NGFR><heavy metal Pb><heavy metal lead><hippocampal><imaging><immunocytochemistry><immunoreactivity><improved><in vivo><indexing><insight><intervention therapy><interventional strategy><macrophage><mesoglia><microglial cell><microgliocyte><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mitochondrial><morphometry><mouse model><multi-electrode arrays><multielectrode arrays><murine model><nervous system infection><network dysfunction><neural><neural degeneration><neural dysfunction><neural function><neural network><neurodegeneration><neurodegenerative><neurodevelopment><neurological degeneration><neuron development><neuronal><neuronal degeneration><neuronal development><normal aging><novel><overexpress><overexpression><p-tau><p-τ><p75><p75 neurotrophin receptor><p75 transcription factor><p75NTR><paired helical filament of tau><perivascular glial cell><persistent infection><phospho-tau><phospho-τ><phosphorylated tau><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post-translational modification of tau><posttranslational modification of tau><preservation><prevent><preventing><primary degenerative dementia><relating to nervous system><release factor><self-aggregate tau><senile dementia of the Alzheimer type><support network><synapse><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau expression><tau factor><tau fibrillization><tau filament><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><transcriptional coactivator p75><transgenic><treatment strategy><uptake><wildtype mouse><τ Proteins><τ aggregation><τ expression><τ phosphorylation>