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NSAID Treatment Targeting

Microglial Inflammation in
Alzheimer’s Disease

Mackenzie Andrews & Kari Severeid


Epidemiology of Alzheimer’s

● Over 5 million Americans over


the age of 65 affected
● Unknown cause
● Current treatment: delay
breakdown of Acetylcholine

(Qiu, C., Kivipelto, M., & von Strauss, E., 2009)


Normal Physiology
Disease of the Central
Nervous System (CNS)
Brain + Spinal Cord

● Neurons transmit
information through (de Heer, 2013)

synapses
Normal Physiology
What if?

(de Heer, 2013)


Normal Physiology
What if?

(Bee, 2014)
Normal Physiology
● Microglia are the
immune cell of the
CNS
○ Ramified (resting)
○ Active
■ Cytokines
■ ROS
■ Proteases
(Roselyne Chauvin, 2017)
Normal Physiology
● Amyloid beta (Aβ) protein works with
microglia
μG Aβ
○ Activate kinase enzymes
○ Protect against oxidative stress
○ Regulate cholesterol transport
○ Regulate antimicrobial activity
Pathophysiology
● Aβ misfolds and forms
plaques
● Membrane receptors of
neurons and astrocytes
affected
● Produces more ROS

(The AD Plan. 2017)


Pathophysiology
● Aβ buildup activates
microglia
● Proinflammatory
cytokines and toxic
products released
● Cytokines encounter
glial cells- more
inflammatory molecules
made
Pathophysiology
● Positive feedback loops
formed
○ (Plaques activate
microglia, vise versa)
● Leads to neurodegeneration
μG Aβ

(Alz.org, 2011)
(pixta.com)
Clinical Presentation
● Memory impairment
● Mild Cognitive
Impairment (with
amnesia)
● Dementia
● Difficult to diagnose

(Senior Care Resources, 2015)


Clinical Outcomes

● Current treatments slow


cognitive decline
● Earlier diagnosis
increases survival time
● No current cure

(Brookmeyer, R., Corrada, M.M., Currlero, F.C., & Kawas, C., 2002)
So What Do We Need?
So What Do We Need?

1. Reduction in
microglial activation

2. Clearance of Aβ
plaques
Anti-Inflammatory
NSAIDs

● Shown to reduce microglial


inflammation
● Can’t cross blood brain
barrier (BBB) in sufficient
amounts
○ Not lipid soluble

(Schreiber, 2016)
Make Flurbiprofen Lipid-Soluble
Flurbiprofen reduces microglial inflammation (Prosperi, et al., 2004)

Lipid Soluble Conjugate

● Polycyclic cage ester prodrug


Make Flurbiprofen Lipid-Soluble
Flurbiprofen reduces microglial inflammation (Prosperi, et al., 2004)

Lipid Soluble Conjugate

● Polycyclic cage ester prodrug


[1] Cookson diketone
[2] Esterify Flurbiprofen

(Van den Berg, M., 2010)

(Adapted from Van den Berg, M., 2010)


Remove Amyloid Beta
EPPS breaks down Aβ aggregates (Kim, H.Y., et al., 2015)

● Orally Safe
EPPS
● Crosses BBB

● Directly dissociates beta sheet


interaction in plaques
Treatment Testing
Flurbiprofen Prodrug + EPPS Co-Administration

1. In vitro microglial stem


cells + Aβ aggregates
2. Mouse model
3. Non-human primate
model
4. Clinical trials
Success Criteria
Flurbiprofen Prodrug + EPPS Co-Administration

● Reduction in ● Same as in vivo


microglial activation ● Cognitive
● Reduction in Aβ improvements
aggregates ● No other side-effects

● Disease progression ● Same as mice


based on NIDA ○ More similar to
diagnostic human disease
guidelines model
Thank You Course
Professor Kelly Stevens Quantitative Physiology
Christine Yoo (TA) BIOEN 498 C