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Evaluation of the Efficacy of Ubisol-Q10 Treatment in a Transgenic Evaluation of the Efficacy of Ubisol-Q10 Treatment in a Transgenic

Mouse Model of Alzheimer's Disease Mouse Model of Alzheimer's Disease

Annie S. Kanwar University of Windsor, kanwara@uwindsor.ca

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Kanwar, Annie S., "Evaluation of the Efficacy of Ubisol-Q10 Treatment in a Transgenic Mouse Model of Alzheimer's Disease" (2016). UWill Discover Undergraduate Conference. 2. https://scholar.uwindsor.ca/uwilldiscover/2016/session1/2

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Efficacy of Ubisol-Q10 Treatment in a Transgenic Mouse

Model of Alzheimer’s Disease

ALZHEIMER'S DISEASE

WHAT IS ALZHEIMER’S DISEASE?

Most common neurodegenerative disorder worldwide, affecting 46.8 million individuals

https://cdn.evbuc.com/eventlogos/40265082/old.jpg

• Most common form of

dementia

• Characterized by the

deterioration of neuronal

synapses and widespread

neuronal death in the

brain1

• This produces enlarged

brain ventricles and cortical

shrinkage

WHAT IS ALZHEIMER’S DISEASE?

http://www.synsys.eu/general-public

https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/alzheimers-disease.html

• Two hallmarks of the disease:

1. Amyloid-β Peptide (Aβ) Plaques

2. Neurofibrillary Tangles containing Tau Protein2

• Tau proteins, found abundantly in the CNS, stabilize axonal microtubules

• Tangles are thought to be due to imbalance between Aβ production and clearance2

WHAT IS ALZHEIMER’S DISEASE?

https://www.alzheimer-forschung.de/alzheimer-krankheit/illustrationen_plaquesfibrillen.htm

http://healthland.time.com/2012/02/03/is-alzheimers-caused-by-contagious-proteins/

• Cholinergic neurons specifically

targeted3

• Specific region may be the nucleus

basalis of Meynert – shown to

deteriorate by more than 75%4

• Neuronal cell bodies in the basal

forebrain3

• Innervate many areas of the

cerebral cortex, thus cognitive

functions such as memory are

compromised3

WHICH NEURONS & BRAIN REGIONS ARE

INVOLVED?

https://psychiatricdrugs.com/neurology/acetylcholine/

https://neuroamer.wordpress.com/page/2/

AD SYMPTOMS

Memory loss

Language

problems

Difficulty with simple tasks

Disorientation

Loss of

reasoning

capacity

Loss of

initiative

Behavioural changes

Emotional changes

Lost objects

Difficulty with

elaborate

thoughts

http://www.doc-advice.com/alzheimers-disease/

CURRENT TREATMENTS• No cure

• Symptomatic relief only

• Drug treatments include:5

• Cholinesterase inhibitors –

ReminylER, Exelon, Aricept1

• NMDA receptor antagonists –

Ebixa (Memantine Hydrochloride)

• Non-pharmaceutical treatments:5

• Music therapy

• Pet therapy

• Aromatherapy & massage

• Natural health products

http://www.superama.com.mx/

http://www.lundbeck.com/pt/produtos/neurologia/ebixa

http://www.founduseful.com/natural-health-products-online-and-over-the-phone/

http://www.indexmundi.com/canada/age_structure.html

• Oxidative stress as a possible mechanism for

neurodegeneration6

• What is oxidative stress?

• Some of the O2 we breathe reacts to form

free radicals destabilize essential cell

components

• Damage known as oxidative stress

• Young, healthy strong compensatory/

defense mechanisms to prevent oxidative

damage

• Ageing weakens defenses such that ROS

accumulate apoptosis can be triggered7

PERHAPS OXIDATIVE STRESS?

http://www.kappit.com/tag/hydrogen-jokes/

WHAT IS CoQ10?• CoQ10, part of the ETC, sequesters electrons and stabilizes the mitochondria.

This reduces the oxidative damage taking place. CoQ10 levels decline with age 9

https://www.pinterest.com/pin/488851734528172000/

ARE ANTIOXIDANTS THE ANSWER?

• Antioxidants have been tested

in the past

• Oil-soluble formulation of

Coenzyme-Q10 was assessed

– showed neuroprotection, but

LOW bioavailability8

• Very high effective doses: 400-

1600 mg/kg/day8

• For 70kg human 112g/day8

http://www.drblayney.com/Medical/

WATER-SOLUBLE UBISOL-Q10

CoQ10 α-tocopherol

PEG

NANOMICELLULAR FORMULATION – UBISOL-Q10

COENZYME-Q10

Our NRC collaborators synthesized a water-soluble formulation of CoQ10, known

as Ubisol-Q10 which is much more bioavailable

http://www.longevitylink.com/coenzyme-q10-supplement-facts-for-healthcare-professionals/

PREVIOUS WORK – PARKINSON’S DISEASE

Environmental Toxin PD Rat Model – therapeutic10

• Senescence: in response to stressors and damage, cells can adopt a

permanent state of cell-cycle arrest

PREVIOUS WORK – ALZHEIMER’S DISEASE12

• Autophagy: a cellular stress response in which there is sequestration

and breakdown of harmful or dysfunctional cellular components

• Engulf damaged proteins/ organelles into autophagosome

• Autophagosome fuses with lysosome autolysosome

• Degradation of cellular proteins

• RT2PCR Array analysis showing genes related to autophagy

PREVIOUS WORK – ALZHEIMER’S DISEASE13

SO WHAT NOW?

Can the Ubisol-Q10 formulation provide

neuroprotection in an in vivo animal

model?

http://www.shutterstock.com/similar-44436877/stock-photo-cartoon-of-a-man-who-is-stressed-out-and-develops-hives.html

TRANSGENIC MOUSE MODEL OF AD

• Transgenic mice, predisposed to develop early-onset AD, were

obtained

• Mice had two mutant human genes inserted:

• Human amyloid-precursor protein (APP)

• Human presenilin-1 (PS-1)

PS-1 (γ-secretase complex) APP Aβ

http://www.nature.com/nature/journal/v425/n6958/fig_tab/425565a_F1.html

Obtained transgenic

mice, predisposed

to early-onset AD

Established control &

experimental groups

Monitored mice for

14 months

Obtained blood

samples & sacrificed

mice to extract brains

Performed biochemical analyses &

immunohistochemistry

EXPERIMENTAL DESIGN

Control – regular drinking water

Experimental – Ubisol-Q10 supplemented

water

• ELISA

• RT2PCR

http://ninjuni.cf/how/how-to-draw-a-cartoon-cat-and-mouse.html http://www.how-to-draw-funny-cartoons.com/cartoon-brain.html

http://www.pd4pic.com/test/ http://www.clker.com/clipart-6247.html

IMMUNOHISTOCHEMISTRY – DECREASED

AMYLOID-Β PLAQUES IN BRAIN TISSUE

Control (Untreated) Ubisol-Q10 Treatment WT

Am

yloi

d

50x

Mag

Con

go R

ed

50x

Mag

1 mm

500 um

ELISA – DECREASED AMYLOID-Β LEVEL

IN SERUM

C o n tr o l T r e a te d W ild typ e

0

1 0 0 0

2 0 0 0

3 0 0 0

S e ru m le v e ls o f h u m a n a m y lo id -ß (1 -4 0 )

Hu

ma

n a

my

loid

-ß (

1-4

0)

in p

g/m

l

RT2PCR analyses still underway

FUTURE DIRECTIONS

• Understand if autophagy can be

restored in the in vivo model

through RT2PCR analysis

• Extend to other genetic models of

AD PS-2 , APP10

• Ultimately hope to develop

Ubisol-Q10 as a treatment for

those struggling with

Alzheimer’s disease

ACKNOWLEDGMENTS• Dr. Siyaram Pandey & Krithika Muthukumaran

• Pandey & Cohen Labs

• Sponsors

REFERENCES1. Alzheimer's disease. (2015, November 8). Retrieved March 25, 2016, from http://www.alzheimer.ca/en/About-

dementia/Alzheimer-s-disease

1. Hardy, J., & Selkoe, D. J. (2002). The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the

Road to Therapeutics. Science, 297(5580), 353-356.

2. Coyle, J. T., Price, D. L., & DeLong, M. R. (1983). Alzheimer's disease: A disorder of cortical cholinergic

innervation. Science, 219(4589), 1184-1190.

3. Whitehouse, P., Price, D., Struble, R., Clark, A., Coyle, J., & Delon, M. (1982). Alzheimer's disease and senile

dementia: Loss of neurons in the basal forebrain. Science, 215(4537), 1237-1239.

4. Treatment options. (2015, October 28). Retrieved March 25, 2016, from http://www.alzheimer.ca/en/About-

dementia/Treatment-options

5. Sikorska, M., Lanthier, P., Miller, H., Beyers, M., Sodja, C., Zurakowski, B., . . . Sandhu, J. K. (2014).

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the

mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: Potential use as an adjuvant treatment in

Parkinson's disease. Neurobiology of Aging, 35(10), 2329-2346.

1. Tieu K (2011) A guide to neurotoxic animal models of Parkin- son’s disease. Cold Spring Harb Perspect Med, 1,

a009316.

2. Sikorska, M., Sandhu, J., & Siyaram, P. (2015, April 16). Solubilized Formulation of CoQ10 for use in Treatment

of Parkinson's Disease. Retrieved from http://www.sumobrain.com/patents/wipo/Solubilized-formulation-coq10-

use-in/WO2015051448A1.pdf

REFERENCES1. Asdf

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9. Ernster, L., & Dallner, G. (1995). Biochemical, physiological and medical aspects of ubiquinone function.

Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1271(1), 195-204.

1. Muthukumaran, K., Leahy, S., Harrison, K., Sikorska, M., Sandhu, J. K., Cohen, J., . . . Pandey, S. (2014). Orally

delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to

paraquat: Potential for therapeutic application in Parkinson’s disease. BMC Neuroscience BMC Neurosci, 15(1),

21.

2. Muthukumarana, K., Smith, J., Jasra, H., Sikorska, M., Sandhu, J. K., Cohen, J., . . . Pandey, S. (2014). Genetic

Susceptibility Model of Parkinson’s Disease Resulting from Exposure of DJ-1 Deficient Mice to MPTP: Evaluation

of Neuroprotection by Ubisol-Q10. Journal of Parkinson's Disease, 4, 523-530.

3. Ma, D., Stokes, K., Mahngar, K., Domazet-Damjanov, D., Sikorska, M., & Pandey, S. (2014). Inhibition of stress

induced premature senescence in presenilin-1 mutated cells with water soluble Coenzyme Q10. Mitochondrion,

17, 106-115.

4. Stokes, K. (2015). Ameliorating Presenilin-1 Associated Autophagic & Mitochondrial Dysfunction with Water-

Soluble Co-Enzyme Q10. Thesis, 43-47.