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BDSRA 2015 CLN3 Kielian

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2015 CLN3 Kielian

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BDSRA 2015 CLN3 Kielian

  1. 1. Neuroinflammation in Juvenile Batten Disease and the Role of an Anti-inflammatory Treatment Tammy Kielian, Venkata R Kakulavarapu, Megan Bosch, Amy Aldrich, Maria Burkovetskaya, and Nikolay Karpuk Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, KEY PROJECTS WHAT THIS MEANS FOR THERAPY ACKNOWLEDGEMENTS - Forest Laboratories, Inc./Actavis/AstraZeneca - Rachel Fallet and Jessica Odvody for excellent technical assistance - Dr. Jonathan Cooper and Nanet Willumsen- King’s College London - NINDS 1R21NS084392-01A1, Bee For Battens- The Saoirse Foundation INTRODUCTION • Juvenile Batten Disease mainly affects brain function in children severely impairing their behavior, intellectual ability, and day-to-day activities. Brain inflammation has been suggested as being one potential factor contributing to neuron loss in Juvenile Batten Disease. • Several brain cells including microglia, astrocytes, and neurons appear dysfunctional in Juvenile Batten Disease. • Our laboratory’s main focus is to understand how brain inflammation, which is harmful to brain function, occurs in Juvenile Batten Disease. • We use the CLN3∆ex7/8 mouse model of Juvenile Batten Disease in our research and are currently testing the effectiveness of roflumilast, an anti-inflammatory drug, to determine if reducing neuroinflamation can result in slowing disease progression and symptoms. Microglia Astrocytes Neurons • Mouse models of Juvenile Batten Disease display early signs of microglia & astrocyte activation • In mice, microglia and astrocyte activation is apparent within 1-3 months of age; however, neuronal death is significantly delayed in comparison (~ 12 months) • These findings suggest that chronic glial activation and subsequent inflammation may influence neuron survival Morales et al., Front. Cell. Neurosci., 2014 • Microglia protect against foreign insults and clear dead cells/debris in the brain • In response to insults, microglia become activated and produce inflammatory cytokines, such as TNF-a and IL-1b • These inflammatory mediators can have neurotoxic effects, and may contribute to JNCL progression. A B • Figure A shows abnormal cytokine production in CLN3∆ex7/8 microglia that kills neurons • Figure B shows that TNF-a production can be reduced in these microglia when treated with an anti- inflammatory compound • Roflumilast (Daliresp©) is a FDA approved phosphodiesterase-4 (PDE4) inhibitor to reduce the risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD) • PDE4 inhibitors have been found in other neurological studies to reduce brain inflammation by inhibiting microglial and astrocyte activation and attenuating microglial proinflammatory cytokine production • We administered Roflumilast to CLN3∆ex7/8 and normal mice orally, once a day, for 6 months starting at 1 month of age • After 3 months of drug treatment, motor function in CLN3∆ex7/8 mice was significantly improved, as indicated by an increased amount of time mice were able to stay on the spinning rotarod • Additionally, astrocyte and microglia activation has been significantly lowered following drug treatment (not shown) • Astrocytes have many functions in the brain and are constantly nurturing neurons to help them function properly • In Juvenile Batten Disease, astrocytes become hyperactive, which can be seen by increased Glial Fibrillary Acidic Protein expression (in green above) • As a result, they do not properly support neurons resulting in neuronal death • Neurons are brain cells that are critically involved in all of our physical and mental activities • Neurons send electrical signals through synapses via specialized structures called axons and dendrites • In Juvenile Batten Disease, some of these neurons die early, which disrupts communication in the brain and eventually leads to cognitive and motor decline Kielian Laboratory • This image shows two different types of synapses, inhibitory and excitatory • In CLN3∆ex7/8 mice , there is an increase in excitatory and decrease in inhibitory synapses • This disrupted ratio can cause neuronal death and seizure activity Inhibitory Excitatory • GFAP, as indicated by the intensity of red staining, is increased in the brains of CLN3∆ex7/8 mice • The Visual Cortex (VC) is responsible for processing information from the eyes • The thalamus (TH) is involved in sleep regulation and is also responsible for relaying sensory and motor signals to other brain regions Overview Rotarod Motor activity