1. ALZHEIMER RESEARCH ADVANCES JOAN SMITH SONNEBORN, PHD. PROFESSOR EMERITUS UNIVERSITY OF WYOMING ZOOLOGY & PHYSIOLOGY

2. VIDEO OBJECTIVES 1 VISUALIZATION OF ALZHEIMER’S DISEASE BRAIN; UNDERSTANDING ALZHEIMER’S DISEASE Objective 2 ADVANCES IN BRAIN VISUALIZATION IN LIVING PATIENTS Objective 3 EXERCISE DELAYING MEMORY LOSS USING AN ALZHEIMER MOUSE MODEL

3. MUST REMOVE STIGMA OF ALZ DISEASE PRODROMAL Alzheimer’s-Earliest Stage. WHERE MICE & NUNS STUDIES MEET REAL CULPRITS STEALING MEMORY? TOXIC AMYLOID; FREE RADICALS HEY! WHY ARE THE ELDERLY TARGETED DIABETES AND ALZHEIMER RELATIONS TOPICS

4. HUMAN DRUG TRIAL UPDATES WHAT SUPPLEMENTS & LIFESTYLES WORK TECHNOLOGIES: NEW DRUGS; NEW BAD GENES TOPICS (CONTD.)

5. WHERE NUN AND MICE STUDIES MEET

6. Plaques & tangles FOUND in nuns & mice not showing memory loss!! In mice*, memory loss without plaques & tangles. *Gandy et al.AUG 2010.

7. CULPRITS IN ALZHEIMER’S DISEASE TOXIC PARTICLES OLIGOMERS; FREE RADICALS.

8. HEY! WHY IN ELDERLY? DECREASE IN PROTECTIVE CELL ENVIRONMENT INCREASE IN DAMAGE ENVIRONMENT

9. AGE DEPENDENT DECREASE IN: 1) PROTECTIVE PROTEINS 2) NERVE COMMUNICATION AGENTS AGE DEPENDENT INCREASE IN: 1) TOXIC FRAGMENTS 2) NOX (noxious) ENZYME PRODUCTION. 3) EXPRESSION OF FAMILY OF DAMAGE GENES. 4) GLUTAMATE EXCESS 5) COPPER EXCESS 6)” AGING GENE” EXPRESSION. WHY IN ELDERLY?

10. DIABETES-ALZHEIMER’S: SHARED PROBLEMS: BOTH HAVE INSULIN RESISTANCE SHOW DECLINE IN KEY ENERGY PATHWAY USE SAME SPLICER TO CUT AMYLOID & INSULIN CONTROL DIABETES; LOSE 5 POUNDS

11. HUMAN DRUG TRIALS FLURIZAN, VACCINE TO INDUCE IMMUNITY BAPINEUZUMAB, (PREFORMED ANTIBODY IMMUNE AGENT) PBT2 COPPER TRANSFER

12. VACCINE FLURIZAN TARGETED A  (AMYLOID BETA) (HBO) INVESTED $200BILLION & 8 YEARS IN FLURIZAN DID SHOW REDUCTION IN PLAQUES & TANGLES BUT HEALTH COMPLICATIONS & NOT SIGNIFICANT EFFECT ON MEMORY LOSS. STUDY DISCONTINUED

13. RECENT HUMAN TRIALS (CONTINUED) BAP; PBT2 USES PREMADE ANTIBODY (BAP), SUCCESS IN SUBPOPULATION NOT CARRYING SUSCEPTIBILITY GENE APO-E-4 ** Phase 3 trial still in progress. PBT2 phase 2 : COPPER TRANSPORTER RESTORES ALZ NEURON PROJECTIONS* & COMMUNICATION PROTEINS LOST IN DISEASE IN MICE Reduces amyloid, improves function on Neuropsychological test Battery (NTB) in 12 weeks IN HUMANS *(humanized monoclonal antibody TO  AMYLOID)- **1/3 OF ALZ NOT CARRIERS; E 4 INTERFERS WITH TAU STICKING TO MICROTUBLES and susceptibility to oxidation; Dendritic spine density and synaptic protein levels in a mouse model Reduces amyloid, improves function on Neuropsychological test Battery NTB in 12 weeks

14. ENVIRONMENT &ALZHEIMER’S ENVIRONMENTAL ENRICHMENT REDUCES AMYLOID IN MICE MODEL RESTORES MEMORY IN MOUSE MODEL NOVELTY, CHANGE IN MENU, CARD GAMES, SCENERY CHANGE, VISITING GROUPS, DANCE INSTRUCTORS, CHILDREN VERSION BINGO GAMES FOR DEMENTIA PATIENTS, ANIMAL VISITS.

15. STRESS REDUCTION MUSIC Ipods with personalized music to soothe or invigorate individual. SUPPLEMENTS, MINERALS AND FOODS: Omega 3, Uridine: Like anti -anxiety Drugs Prozac and SSRI Inositol: Like Valium EXERCISE

16. SUPPLEMENTS? INOSITOL, OMEGA-3 FATTY ACIDS, URIDINE, CURCUMIN, ANTIOXIDANTS, VITAMIN D, C, E, FOLATE, LIPOIC ACID, RESVERATROL

17. ANTI DEPRESSION SUPPLEMENTS, SUPPLEMENTS: URIDINE AND OMEGA-3 TOGETHER MATCHED WITH EFFECTS OF PROZAC AND SSRI’S DRUGS IN MICE* URIDINE stimulate synthesis of CHOLINE, OMG increase membrane fluidity and reportedly have antidepressant effects in humans, alone and in combination with uridine. URIDINE FOODS: Organ meats (liver, pancreas),Tomatoes, Brewer’s yeast, Beer, **Broccoli Omega 3 (polyunsaturated fats) foods:cold water fish, such as salmon, or flaxseeds, walnuts, winter squash *. Omega 6 Omega-6s contribute to inflammation in the body, while omega- 3 modulates **Carlezon et al., 2005 Biol Psychiatry 57 (4): 343–50. ***Yamamoto et al., Metab Clin Exp 51 (10): 1317–23.

18. ANTI ALZHEIMER SUPPLEMENT VITAMIN D & FOLATEe VITAMIN D : ↑ Transports out cell garbage,↑ Regulates nerve health pathways; No D intensifies deficit in spatial learning in ALZ patients.** FOLATE Required : brain health, function and development ↓ blood pressure and arterial stiffness Supplement in 60 year olds reduced ALZ risk after 10 years. Advanced Alzheimer’s Disease lowest folate levels. Deficiency in institutions & nursing homes: people with absorption problems such as ulcerative colitis and people taking certain medications e.g., methotrexate. dark green leafy vegetables oranges, lentils, beans, asparagus, broccoli, cauliflower, liver and brewer's yeast. *

19. CELL MEMBRANE AND INSULATION Saturated fats and cholesterol are significant portion of insulation (myelin sheath) around nerve fibers. Born with 100% phosphatidylcholine (lecithin); only have 10% in elderly major constituent of all cell membranes including nerve cells Major Source of lecithin egg yolks

20. SUPPLEMENTS INOSITOL,and choline is lecithin- ingredient in cell membrane, signal processes, increase acetylcholine and serotonin.↑ positive mood ↓ copper excess, ↑ hair growth. Treats schizophrenia and hypoglycemia. Mimics Valium. Also acetylcysteine: glutamate receptor

21. ANTI-ALZ SUPPLEMENTS OMEGA-3 FATTY acids ↓ amyloid & tau protein, EPA low in suicide patients, DHA OMG-3s URIDINE (CHOLINE PRECURSOR): ↑ acetylcholine, repairs synapse membrane in neurons, membrane, damage= dementia Omega 3 and Uridine supplements are antidepressant, like PROZAC and SSRI in bipolar disorder, reduces amyloid CURCUMIN (Tumeric,curry, seasoning)*, antioxidant, promotes healthy gene expression.

22. CHOLINE and membrane FOODS CHOLINE PRECURSOR TO ACETYLCHOLINE Foods with inositol, and uridine Lecithin membrane precursor eggs.

23. SIRTUINS: RESVERATROL Anti Aging supplement. “ Molecule modifier”s required for participation/ initiation in major metabolic processes (Deacetylases) Activates “Notch” gene pathway for protection against stress, nerve damage,and inhibition of enzyme that generates amyloid. Crossed AD mouse with high sirtuin mouse- onset of memory loss delayed*

24. LIPOIC ACID* & ACETYL CARNITINE *REDUCED MEMORY DEFICITS IN ALZHEIMER MICE -STRONG ANTIOXIDANT Acetyl L carnitine : mitochondrial and energy generator, utilizes fatty acid, neuroprotective, memory enhancer; in AD studies

25. SUNDOWNER* SNACK? BANANA, PAPYA, DATES (without skin),, ORANGES**, MELON** increase serotonin, and acetylcholine. No wheat or rye Promotes serotonin (GOOD MOOD) AND breakdown to melatonin (sleep enhancer) – circadian rhythm hormone and “jet lag intervention” *describes the onset of confusion and agitation that generally affects people with dementia or cognitive impairment and usually strikes around sunset. ** inositol source neuronal membrane and neurotransmitters

26. CHOCOLATE AND HEALTH 23.6 million people will die from cardiovascular disorders. High chocolate consumption (5x/week) associated with 30% risk reduction in: heart diseases, stroke, ie., lowered blood pressure, cholesterol, atherosclerosis, and insulin resistance. Increased brain blood flow in elderly.*Dramatic effect at least in part due to triggering release on Nitric oxide (NO)**

27. Chocolate & Theobromide Milk chocolates 20-50% less theobromide (caffeine like chemical) than dark. Action :: diuretic, stimulant, blood pressure relaxer, allows blood flow, relax bronchi muscles in the lungs- used in cough medicine. Acts on the vagus nerve, which runs from the lungs to the brain. Poison for dogs and horses and humans that metabolize theobromine slowly, including some elderly.

28. EXERCISE IN ELDERLY Falls: leading cause of injury, death and disability among persons 65 years and older By 2020, falls in over 65 about $43.8 billion/yr. Weight training: increases bone density and bone facture risks. Bone loss 5% per decade after 40. Age associated muscle loss reversible Number of falls from frail women 80 reduced by half in a year with weight training. Some over 90, used cane instead of walker, could get out of chair, and increased mobility. " ACSM's Health & Fitness Journal"; Benefits of Physical Activity in Older Adults; Angela Fern; Sept/Oct 2009, * Fiatarone Tufts University in Boston

29. Exercise in Elderly IN NURSING HOME (cont) Reduces prescriptions, doctor visits, emergency calls, orthopedic devices cost, and extent of care needed. Increases mobility and decreases deficits in ADLs; can feed themselves, get out of chair. Improves cognition, mood, and self image. Improves muscle mass, joints, and strength for balance Provides intervention in diabetes, osteoporosis, depression, and obesity and required associated care requirements.

30. EXERCISES CHAIR STAND, STANDING LEG CURL, SIDE HIP RAISE, BICEP CURL, OVERHEAD PRESS, UPWARD ROW, TOE STAND** ANKLE & WRIST WEIGHTS LESS FAT,MORE MUSCLE, BONE LOSS PREVENTED OR REVERSES LOSS, INCREASES, STRENGTH, ENERGY, BALANCE, AND FLEXIBILITY. *Miriam Nelson, Ph.D. 2 “Strong Women Stay Young” 2 sessions/week ISBN 0-553-38077-X

31. TELOMERES, ADULT STEM CELLS, & REPROGRAMS TELOMERES CAPS ON CHROMOSOMES SHORTER CAPS ≈ SHORTER LIFE SPAN REPLACE CAPS, REPAIR &REJUVENATE AGE DAMAGED NEURONS ACTIVATION OF ADULT CELL REGENERATIVE CAPACITY

32. REGENERATIVE MEDICINE TAP INTO HORMETIC RESPONSE (a little bit of bad is good, a lot is bad) Major protective pathways are inducible by stress for repair and regeneration that respond to immediate threat, but repair age damage as well even in the very old. Response can be triggered by known small molecule triggers.

33. ALTERNATIVE METHODLOGY AGING INTERVENTIONS ROLE OF TELOMERES ADULT STEM CELLS HORMESIS

34. TELOMERE REPLACEMENT REVERSES AGING ENGINEERED AND “KNOCK-OUT” AND INDUCIBLE KNOCK IN” MOUSE RESULT: ACCELLERATION OF AGING REVERSED IN ALL ORGANS BY INDUCING REPLACEMENT OF TELOMERES.

35. ADULT STEM CELLS STEM CELLS THROUGHOUT ADULT CAPABLE OF REJUVENATION WITH MASTER SWITCHES SIGNALS BEST SOURCES: UMBILICAL CORD, AMNIOTIC FLUID, WISDOM TEETH, AND GUM TISSUE. DURING DEVELOPMENT DIFFERENTIATION TO CELL TYPE; NOT UNIDIRECTIONAL-CAN REVERSE.

36. CONCLUSION DELAY METABOLIC AGE VULNERABILITY ENHANCE PROTECTION STRATEGIES AGAINST CULPRITS THAT STEAL PRECIOUS MEMORIES. REDUCE CONCENRATION ON PLAQUES AND TANGLES EXPLORE REGENERATIVE STRATEGIES

37. CONCLUSION: HOPE THERE IS REAL PROMISE OF DELAY OF ONSET AND PROGRESSION OF ALZHEIMER’S DISEASE IN OUR IMMEDIATE FUTURE.

38. 307-766-2829 Please visit our website at: http://www.uwyo.edu/geriatrics/ ______________________________ Wyoming Geriatric Education Center