Peter H. Massey

1. A Correlation Between Alzheimer’s and Parkinson’s: Inflammatory Response to Endogenous Neuro-protective Mechanisms Peter H. Massey

2. “Brain Attacks” • CVDs are the principal cause of death in Western civilizations, accounting for more than 40% of all deaths. • Cerebrovascular Disease – disease of blood vessels supplying the brain - Sustained hypertension - narrow, stiff, deformed • Stroke – loss of blood supply – leads to paralysis • Aneurysm – blood filled dilation of blood vessel – if ruptured extremely harmful • Ischemia – temporary paralysis http://medicalimages.allrefer.com/large/stroke.jpg

3. Protein Activation • Basal ganglia - dopamine & acetylcholine - transmission of nerve impulses http://www.nature.com/nrn/journal/v2/n7/images/nrn0701_492a_f2.gif http://stemcells.nih.gov/StaticResources/info/scireport/images/figure82.jpg

4. http://www.about-dementia.com/articles/images/ParkinsonsDopamine.jpghttp://www.about-dementia.com/articles/images/ParkinsonsDopamine.jpg Parkinson’s Basics • Parkinson's disease - between the ages of 50 and 65 - 1% of the population

5. Symptoms • Alzheimer’s • Dementia: both long term and short term in later stages of life • Loss of reasoning & logic • Parkinson’s • Slowness of voluntary movements, especially in the initiation of such movements as walking or rolling over in bed • Decreased facial expression, monotonous speech, and decreased eye blinking • A shuffling gait with poor arm swing and stooped posture • Unsteady balance; difficulty rising from a sitting position • Continuous "pill-rolling" motion of the thumb and forefinger • Abnormal tone or stiffness in the trunk and extremities • Swallowing problems in later stages

6. Parkinson’s Linked to Alzheimer’s • Alpha-synuclein - accumulate into Lewy bodies inside nerve cells - found in the amyloid plaques in Alzheimer's disease • Alpha-synuclein - binds to membranes on nerve cells – lipids (Deniz, March 2009 - PNAS) http://len.epfl.ch/webdav/site/len/shared/import/migration/parki1_1.jpg

7. Inflammatory Response • Inflammation - response to infection or injury - Damaged tissue releases chemicals - attract white blood cells - Cytokines - accelerate inflammation http://lpi.oregonstate.edu/ss03/lipoicacid.html

8. Inflammatory Response (continued) • Inflammatory cytokines - stimulate production of adhesion molecules - adhesion molecules prone to atherosclerosis - important target for treatment of atherosclerosis & CVD • Inflammatory molecules - recruitment of white blood cells into the blood vessel wall - abnormal foam cells & atherosclerotic lesions • Alpha-lipoic acid - ‘metal chelators’- inhibit white blood cell recruitment - preventing infection and inflammation - reducing oxidative stress - bolstering antioxidant defenses http://www.nature.com/nrn/journal/v7/n1/images/nrn1829-f3.jpg

9. Inflammation Linked to Parkinson’s • Nurr1 - transcription factor • Nurr1 protein - microglia & astrocytes - Microglia are macrophage-like cells - immune defense in the central nervous system - Astrocytes - large star-shaped support functions (keep cell alive) • Absense of Nurr1 - inflammation increased - toxic effect on those neurons University of California - San Diego (2009, April 6). Protein Protects Neurons In Brain From Damage Due To Inflammation. ScienceDaily.

10. http://www.neuro-zone.com/writable/content_attachments/neurons%20in%20network.jpghttp://www.neuro-zone.com/writable/content_attachments/neurons%20in%20network.jpg http://www.amicusvisualsolutions.com/obrasky/06015_02W.jpg Observing Brain Activity • Brain Culture – advantageous – one specimen over prolonged period • Fluorescence microscopy • Induced axonal damage • Inflammatory response initiated • Axonal regeneration observed

11. Treatment • Balance of the neurotransmitters acetylcholine & dopamine • Success with experiments involving operative procedures - too invasive http://www.herbsandtinctures.co.uk/images/maca-capsules.jpg

12. α-Lipoic Acid • Anti-inflammatory: cell signaling processes; sensitivity, metabolism, and stress response • Inflammation & cell cycle control • Reproduces endogenous anti-oxidants: glutathione, vitamin C and E • Removes superoxide anions, hydroxyl radicals, and other toxic ROS from body (the cell) • Both hippocamal regions and basal ganglia (hydrophilic & hydrophobic) • Related to inflammation & oxidative stress http://aging-management.com/images/Lipoic-acid-2D-skeletal.png

13. Sepsis Hotchkiss and Nicholson Nature Reviews Immunology advance online publication; published online 13 October 2006 | doi:10.1038/nri1943

14. Sepsis-associated Encephalopathy • Feinstein Institute for Medical Research Dr. Sangeeta Chavan - sepsis Dr. Kevin Tracey – Vagus nerve stimulation block inflammatory response leading to disease (sepsis) • Encephalopathy – infection of blood – brain dysfunction (may be due to direct infection of spinal cord) - Sepsis – whole body inflammatory state http://focosi.altervista.org/sepsis.jpg

15. Selected References Baier, Anne DeLotto. “In Earl Diagnosis of Alzheimer’s Disease, MRI Brain Scans Accurate.” Medical News Today. 25 December, 2008. Bier, Ethan. “Antioxidants put Parkinson flies back in the PINK.” The National Academy of Science of the USA. 2006. Clark et al. “Mitochindria, flies, and Parkinson’s disease.” Nature, 441, 1162-1166. January 2009. Dawson, Ted. “Protein Target for Parkinson's’ Disease.” Johns Hopkins’ Insittute for Cell Engineering. 2 Dec, 2005. DeLegge, Mark H. “Neurodegeneration and Inflammation.” Nutrition and Clinical Practice. Vol. 23, No. 1, 35-41. 2008. Feany, M.B. “A Drosophila Model of Parkinson’s Disease,” Nature. 404, 394-398. March 23, 2000. Georgetown University Medical Center (2008, September 11). “How Parkinson’s Develops: Protein Found That Regulated Gene Critical to Dopamine-releasing Brain Cells.” Science Daily. Hald, Andreas et al. “Oxidative stress and inflammation in Parkinson’s disease: is there a casual link?” Experimental Neurology. Vol. 193, Issue 2. June, 2005. Hunter, Randy L. et al. “Inflammation Induces Mitochondrial Dysnfunction and Dopaminergic Neurodegeneration in the Nigrostriatal System.” Journal of Neurochemistry. Vol. 100, No. 5. 2007. Journal of Clinical Investigation (2008, January 7). “Breaking Down the Potential Molecular Mechanisms Underlying Parkinson Disease. Science Daily. Lipton, J. M. et al. “Marshaling the Anti-inflammatory Influence of the Neuroimmunomodulator α-MSH.” News Physiology. Sci. Vol. 15. August, 2000. Lu xin, Peter Richardson. “Inflammation near the Nerve Cell Body Enhances Axonal Regeneration.” The Journal of Neuroscience. 11(4): 972-978. April, 1991. Majno, Guido. “Chronic Inflammation: Links with Angiogenesis and Wound Healing.” American Journal of Pathology. Vol. 153. No. 4. October, 1998. Masliah, Eliezer et al. “β-amyloid peptides enhance α-synuclein accumlation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease.” Journal of Neurobiology. Vol. 98. No. 21. October 9, 2001. Maczurek, A. “Lipoic Acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease.” 2008. Northwestern University (2006, January 19). “Gene Tharpy ‘Turns Off’ Mutation Linked to Parkinson’s Disease. Science Daily. Trivedi, Bijal P. “Exploring Parkinson’s Disease, With a Little Help From Flies.” Genome News Network. March 24, 2000. University of California (2009, April 6). “Protein Protects Neurons in Brain From Damage Due to Inflammation.” Science Daily. Weiss, R. “Human Brain Neurons Grown in Culture.” Science News. May 5, 1990. Whitehead Institute for Biomedical Research (2009, March 9). Calculating Gene and Protein Connections in Parkinson’s Disease Model. Science Daily. Yang Q, et al. “Regulation of Neuronal Survival Factor MEF2D by Chaperone-Medicated Autophagy.” Science. Jan 2, 2009. Zhang, Weijian. “The Role of Lipoic Acid in Inflammation and Atherosclerosis.” Micronutrient Research for Optimum Health. May, 2003. Zigmond, M.J. “Triggering Endogenous Neuroprotective Mechanisms in Parkinson’s Disease: Studies With a Cellular Model.” Journal of Neural Transmission. 2006.