Bi-directional communication between astrocytes and neurons regulates synaptic formation, synaptic strength, and participates in the regulation of neural circuitry by coordinating activity among groups of neurons. Astrocyte dysfunction in the settings of HIV-infection, and other neurodegenerative conditions has been postulated to disrupt the activity of neural networks involved in memory and executive functions. Although HIV-associated perturbations in the composition and quantity of various cytokine, chemokine and growth factors released from astrocytes have been demonstrated, these observations have thus far been insufficient to explain how astrocyte stress contributes to neuronal dysfunction. These questions are particularly important in the era of Antiretroviral Therapy (ART), where reductions in neuronal connectivity, synaptic simplification and reductions in dendritic complexity are thought to be primary contributors to cognitive impairments in HIV- infected individuals. Advancements in our understanding of the biology of extracellular vesicles have begun to implicate glial released microvesicles as primary mediators of glia to neuron communication. In preliminary experiments we provide evidence that a variety of stimuli can induce astrocytes to shed microvesicles. The molecular cargo of astrocyte-shed microvesicles was complex and contained more than 200 distinct proteins, 100 miRNA, and hundreds of bioreactive lipid species. Moreover, the protein, miRNA and lipid composition of astrocyte exosomes was modified by the stimulus used to induce release. These astrocyte-shed exosomes directly interacted with neurons to modify neuronal structure and function. Based on these preliminary findings we reasoned that a scientific focus on any one protein, lipid or miRNA would be unlikely to produce a true representation of the functions regulated by this complex signaling vesicles. Therefore, we used bioinformatic and systems biology approaches to understand how the protein, miRNA and lipid composition of exosomes interacts to regulate neuronal signaling pathways identified by whole genome sequencing of target neurons. In this application we focused our efforts on a small number of the identified pathways. In particular we concentrated on neural pathways associated with synapse formation, spine formation, and neurite outgrowth, as these neuronal structures appear to be damaged in many HIV infected individuals. The goals of this application are to understand how endogenous excitatory stimuli and inflammatory stimuli associated with HIV-infection modulate the cargo of astrocyte-shed exosomes and how these exosomes regulate/dysregulate the structure and function of their target neurons.

Public Health Relevance

Reductions in brain volume, neural damage and cognitive deficits still occur in HIV infected individuals despite cART. Our preliminary findings suggest tha exosomes released from stimulated astrocytes regulate structural and functional aspects of learning and memory in adjacent neurons. Inflammatory mediators and HIV-proteins promoted the release of exosomes that damaged dendritic spines, while excitatory transmitters (ATP and glutamate) induced the release of exosomes with neurotropic properties. A greater understanding of how exosomes impact neuronal structure and function will open new areas of investigation in neurobiology and in neurodegenerative research, and could identify novel targets/strategies for therapeutic interventions that regulate or mimic these endogenous nanovesicles.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH110246-02
Application #
9258500
Study Section
Special Emphasis Panel (ZRG1-AARR-K (52)R)
Program Officer
Rao, Vasudev
Project Start
2016-04-10
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$364,500
Indirect Cost
$139,500
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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