Neuroinflammation contributes to neuron loss in juvenile Batten disease. The study tests the anti-inflammatory drug roflumilast in a mouse model of the disease. Researchers found that roflumilast treatment for 3 months improved motor function in mice and reduced microglia and astrocyte activation associated with neuroinflammation. The results suggest reducing neuroinflammation through anti-inflammatory drugs may help slow disease progression in juvenile Batten disease.

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, tkielian@unmc.edu
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