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Summary and brief description of the experiment: Prevention/delaying of Alzheimer’s

Summary and brief description of the experiment: Prevention/delaying of Alzheimer’s Disease before the manifestation of the clinical phenomenology.

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Summary and brief description of the experiment: Prevention/delaying of Alzheimer’s

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  1. Summary and brief description of the experiment: Prevention/delaying of Alzheimer’s Disease before the manifestation of the clinical phenomenology The purpose of this study is to experiment how strongly a group of antioxidants as mitochondrial supporters, DNA/RNA protectors, protein and DNA repairing agents, free radical scavengers, metal chelating agents, enzymatic stimulators/inhibitors, vitamins and others, has the positive effect of preventing and/or delaying the progression a neurodegenerative illness as Alzheimer’s Disease, once it is subclinical, in the very initiation or even unsuspected. Oxidative stress is considered as early inducer of AD in genomic vulnerable individuals and an essential Neurochemical phenotype to the pathogenesis of AD. – Nevertheless, many clinical studies and mice models of AD, even in the very early Phases have not given satisfactory results with the chronic administration of particularly only one or two antioxidant agents or free radical chelating agents as most of the studies show. Our hypothesis considers the study of 4 groups of 30 of 40 elderly individuals including control who will be given 7(seven) to 12(twelve) of the mentioned supplements for a period of 2(two) - 4(four) years. Chronic depression/anxiety is associated with AD and may have some alike Molecular and cellular mechanisms, including some common points as oxidative stress as shown in some studies. This pathology will be considered in the experiment, but not Alzheimer’s disease neither MCI. These elderly people should have only a suspect whether some mild cognitive decline found in clinical and neuropsychological examination is due to age or to a beginning of a neurodegenerative illness, as very often happens in psychiatric or psychogeriatric clinic. The preventive, protective or therapeutic influence of these nutrients or supplements together with antidepressant drugs, will be compared with the power of antidepressant drugs together with memantine and a cholinesterase inhibitor. Every 8 months all individuals composing the groups will be assessed for blood tests, Alzheimer’s disease markers, some neuropsychological scales and clinically investigated for cognitive, humor, orientation, and other psychiatric and neurological symptoms. It is to study the viability and significance to assess neuroimaging and CSF markers data. All data will be compared inter groups at the end of each period of 8 months, after all the results of the new assessment be obtained.

  2. 1 – Four groups – A, B, C, D – of elderly people about 70 years old, matched for socioeconomic status, instruction, male-female genders, randomly selected. GROUPS OF N = 30, 40 or 50 SUBJECTS. 2 – Groups B C and D must have history of chronic depression-stress-anxietyand use of antidepressant drugs form more than 6 months. No other severe chronic diseases as cancer, diabetes, cardiovascular illnesses, stroke, autoimmune-metabolic diseases, arteriosclerosis. No cognitive or other clinical sign of dementia or MCI is to be found. 3 - Group A – Is a control group with no chronic somatic neither serious psychiatric-cognitive illnesses or chronic mild depression. Group D is a healthy control group. 4 – nevertheless, there must be some cognitive or other normal age decreasing signs, that give the clinical impression of some concealed, insidious and neurodegenerative disease leading to doubt or indecision in the diagnosis. 1 - At the beginning of investigation all groups A,B,C,D, undertake some series of blood, plasma and neuroimaging procedures that may be important for Alzheimer’s disease. These procedures should be studied and selected in reason of their viability and economical resources. If confirmed AD diagnosis under DSM-IV in any of the subjects the subject must be substituted or simply dispensed. 2 – The importance of Hamilton scale for depression is to be studied if essential in the project, as it is not indispensable that the subjects be in depressive crisis at specific periods of the experiment including this first one. As mentioned, the history of long term major depression and/or dysthymia – with the detail of serious life adversities (if there are) – are required. 3 – Groups A, B and C will receive daily for TWO – FOUR YEARS (to be studied) - antidepressant drugs to be selected or in coherence with those they were taking for their depressive syndromes. The AD could be changed to be alike the one used in the experiment.

  3. 4 – GROUP B WILL RECEIVE DAILY during the established time (2-4 years): a combined aggregate of brain supplements as antioxidants, vitamins, mitochondrial supporters, metal and free radical scavengers, DNA/RNA/PROTEIN repairing agents, enzyme stimulators/inhibitors, cofactors. (These nutrient supplements will be summarized below: could be between 7 to 12 agents given through the more easely and economic way, DAILY. 4.1 - This group will receive DAILY , for the same time (2-4 YEARS) the NMDAR antagonist MEMANTINE and the acetylcholinesterase inhibitor DONEPEZIL. 4.2 – This group will also receive DAILY for the same time an ANTIDEPRESSANT DRUG, PREFERENTLY A SELECTIVE NOREPINEPHRINE AND SEROTONIN OF REUPTAKE INHIBITOR (NSSRI). 5 – GROUP C : WILL RECEIVE DAILY the same amount and doses of vitamins, antioxidants and all other protective brain agents given to group 4. for the same time (2-4 years) 5.1 – this group will receive the same antidepressant for the same time as given in group 4(4.1). 5.2 – no memantine neither donepezil will be given to this group

  4. 6 - GROUP D: WILL RECEIVE ONLY THE TRADITIONAL TREATMENTS FOR DEPRESSION AND FOR PREVENTION OF SUSPECTED MCI OR AD, FOR THE SAME TIME (2 -4 YEARS) AND SAME DOSAGES: 6.1 –MEMANTINE DAILY AND AS GIVEN IN GROUP 4 (2 -4 YEARS) 6.2 – DONEPEZIL DAILY AND GIVEN AS IN GROUP 4 (2 -4 YEARS) 6.3 – THE SAME ANTIDEPRESSANT DRUG USED BY THE OTHER GROUPS ON THE EXPERIMENT and in thesamewayanddosasge. 7 – An E GROUP with alike phenomenology, that would receive only the same nutrients and supplements in equal doses and frequency as the other B,C and D groups - but no antidepressants, no memantine and no donepezil - for identical period of time, should be studied. Probably, by ethical and medical reasons it would be improbable or impossible.

  5. PLAN SCKETCH OF THE EXPERIMENT

  6. 1 – It is possible to give all supplements orally and with exact doses mixed in only one or two capsules what facilitates the continuity, disposes all data for comparing and effects, with better clearing than dietary nutrients – difficult to assess and to evaluate for 2 – 4 years 2 – The doses must be carefully verified and measured accordingly to the best effect and not menace of toxicity. Nevertheless high sub-toxic dosages should be administered when possible and mild or moderate amounts when suggested by other studies 3 – The interaction of theses herbal, oil and vitamin supplements must be also studied to avoid unexpected results and interference with other enzymatic systems and molecular pathway pathways. 4 – Molecular mechanisms of action are partially known or not clear at all. Then, It is possible to find redundancy in the mechanisms of action of two or more supplements. This condition should also be studied. 5 – Some unveiled mechanisms in recent studies will be briefly mentioned, related to each one of the agents. 6 – The positive aspects and key reasons of this simultaneous administration of seven to twelve (8 – 12) substances together with antidepressants and other neurotransmitter control agents have the possibility to acting through “CLOSING THE CIRCLE AROUND”, trying strongly to counter oxidative stress, β-amyloid and/or α-synucleinaggregation, DNA damage, protein, lipid and glycoprotein oxidation, impairing of neural functions, enzymes, synapses and plasticity –- the essential neuropathogenesis of neurodegenerative diseases (and supporting RNA, DNA and enzymatic antioxidant systems before the disease manifests itself clinically or begins to ruin the life of carrier patients. We believe that one of the main reasons that the results of administering one, two or even three supplements have some doubtful results is because the neuropathogenesis signaling is not completely covered into the brain, “giving a window for some pathways to escape and continue their neuron destruction”. 7 – In a series of recent studies it was demonstrated the superiority of the natural mixture of herbs and other substances acting on the brain, what may clear that many simultaneous interaction signaling molecular pathways are expressed not only in the CNS, but the whole organic systems of the body. Neurons“deal with hundreds of natural molecular signaling agents; we believe twelve more administered externally with all the carefulness needed will not hinder or damage the brain”. 8 – The enormous difficulties that elderly people have to maintain persistently for years healthy diets with all the needed antioxidant supplements, vitamins and other nutrients eaten in diets for years doubtless fall out of experiment control. This alone may justify the experiment, even with certain doubts about synthetic and orally administered substances. 9 – This experiment allows us to compare the antioxidant and the other mentioned supplements with a glutamate antagonist – memantine – and with an acetylcholinesterase inhibitor - donepezil; and to assess the effects of the anti depressants – very commonly used in the geriatric andpsychiatric therapeutics for cognitive and emotional impairment. COMMENTS ABOUT THE PROJECT

  7. 10 Figures of this study approach the bases of the experiment schedule 10 Oxidative Stress and Neurodegeneration: An Inevitable Consequence of Aging? Implications for Therapy . . . . . . . . . . 305 Roberto Rodrigues, David J. Bonda, George Perry, Rudy J. Castellani, Gemma Casadesus, Hyoung-gon Lee, Hyun-PilLee, Xinglong Wang, Xiongwei Zhu, Robert B. Petersen, and Mark A. Smith. (Michael S. Ritsner Editor: Brain Protectionin Schizophrenia, Mood and Cognitive Disorders).

  8. 1 – METABOLIC-ENERGETIC “AGING CASCADE” Fats Carbohydrates Proteins – Aminoacids OtherNutrients oxidation Krebs Cycle Respiratorychain mitocôndria extra-mitocondrial sources ofreductorequivalents Role oftherespiratorychainofmitochondria in theconversionoffoodenergy to ATP. Oxidationof major foodstuffs leads to thegenerationofreducingequivalents (2H) that are collectedbytherespiratorychain for oxidationandcoupledgenerationof ATP

  9. 2 – NEUROBIOLOGICAL-OXIDATION “AGING CASCADE” ACTIVATION INHIBITION OXIDATIVE STRESS ANTIOXIDANTS Transcriptional continuityerrors • DNA continuous • lesions , proteins • lipids, glycoproteins, • othersubstrates MAIN FREE RADICALS Slow neural and stress oxidation ½ o2 Ageing leads to decrease ofantioxidantdefesesandconsequently to a robustfree-radicalactivityand OS ROS RNS e H2O

  10. 3 – OXIDATIVE STRESS-β-AMYLOID- “AGEING CASCADE” ? Genetic abnormalities: mutant alleles of proteins (TAU, APP, PS1, PS2, ApoE4, α2MG), enzymes, macromolecules, lipoproteins, etc. Transcriptional continuity errors(?) e FREE OXYGEN AND NITROGEN RADICALS, (ROS, RNS), OTHER OXIDANTS (METALS) Mitochondrial DNA Stochasticmutagenicity, membranepathology AEROBIC (o2) RESPIRATION Senile plaques neurofibrillary tangles, other pathological and structural impairments ? Glucocorticoid “cascade”glutamate- Calcium- IC influxexcitotoxicity OXIDATIVE AND NITROSATIVE STRESS Life circumstances, mental long-term disturbances, (chronic depression ?), diseases, sepsis, cancer ? EXCESSIVE FORMATION OF FREE RADICALS. DECLINE IN CLEARING ANTIOXIDANT AGENTS ? FIBRILLATION, AMILOID BETA deposition, protein aggregation Mutant alleles, in the related genes of enzymes, proteins (TAU, APP, PS1, PS2,ApoE4) and parallel macromolecules - chaperons as compensatory defenses/responses against oxidative and nitrosative stress, ABNORMALITIES IN: TAU PHOSPHORYLATION, APP, ApoE4, PS1,PS2 , α2MG, COMPENSATORY –METABOLIC AND STRUCTURAL FUNCTIONS NEURON and GLIAL DEATH demented senility ALZHEIMER TYPE

  11. Hypothesis of an Illustrative model summarizing how a long-life stress (in our case MDD) could induce aging and AD through OS CORTISOL CASCADE HIPPOCAMPAL NEURAL METABOLISM AND NEUROGENESIS HYPOTHALAMIC CORTICOTROPHIN RELEASING FACTOR CHRONIC STRESS - ANXIETY MAJOR DEPRESSIVE DISORDER CORTISOL AGING AND METABOLIC ENERGETIC CASCADE IN DEPRESSION/STRESS GLUTAMATE NMDAR - AMPAR 5-HT,DA, GLUTAMATE GABA,NE , DYSREGULATION GLUCOSE UPTAKE BDNF ATP + METABOLIC NEURAL ENERGY HIPPOCAMPAL ATROPHY Ca NEUROBIOLOGICAL-OXIDATION AGING CASCADE AND DEPRESSION ROS + NRS FREE RADICALS NATURAL AND NUTRIENT ANTIOXIDANTS AND ENZYMES SIGNALING CELL DOWN STREAM PROCESSES OXIDATIVE STRESS BNDF Neuronal nucleus DEPRESSION And BDNF AGING – AD CASCADE CLEARING PROTEINS AND CHAPERON MUTATIONS: APP, PS1, PS2, TAU, ApoE MUTATIONS CREB NUCLEAR DNA/RNA TRANSCIRPTION AND TRANSLATION PROTEIN STRUCTURAL AND FUNCTIONAL CHANGES mitochondria ? Mitochondrial DNA damage, stochastic mutagenicity. electron CTR enzymes and complexes mutations MITOCHONDRIAL DAMAGE – NEURAL APOPTOSIS /NECROSIS CELULAR RESPIRATION FAILURE , HYPOXIA HEREDITARY, AND FAMILIAL; TRANSCRIPTIONAL CONTINUITY BIAS (?) MUTATIONS DNA, RNA PROTEIN DAMAGE OXIDATIVE STRESS, TAU AND AMYLOID AGING CASCADE IN DEPRESSION DEMENTED SENILITY OF THE ALZHEIMER TYPE COMPENSATORY ACCUMULATION OF AMYLOID –TAU HYPERPHOSPHORYLATION – SENILE PLAQUES, NFTS, antioxidant threshold exceeded AGING

  12. CLINICAL RELATIONS: AGING, MCI and ALZHEIMER’S DISEASE – INTERESTING DATA and possible bias. That may justify the allusion of AD as: “Demented Senility Alzheimer Type” IN LATE ONSET AD (LOAD) 1 - Random choice of 100 normal elderly people 65+y.o. (no ins, no outs) 2 – 65+ year old: AD about 5% = (of 100)= 5 AD. 100-5 = 95 no AD PEOPLE 3 – 75+ year old: AD About 10% (of 95) = 9.5 AD. 95-9.5 = 85.5 no AD PEOPLE 4 – 85+ year old: AD about 25% (of 85.5 )= 21.4 AD. 85,5–21,4= 64.1 no AD PEOPLE 5 – 95+ year old: AD about 45% ( of 64.1) =28.9 AD. 64.1 –28.9 = 35.2 no AD PEOPLE 6 – 100+ year old: AD about 50% ( of 35.2) = 17.6 AD. 35.2 -17.6 = 17.6 no AD PEOPLE Following a cohort for 35+ years of life after age 65, if we are guided by world recognized statistics obeying a median profile, we will reach to the impressive and almost unbelievable results which show that of 100 healthy individuals – supposing all of them live till 100+ years of age and no other persons enter in this closed system – 82.4 persons will be AD carriers and ONLY 17.6 will remain AD free at that age!

  13. Anillustratedsupposition Lets suppose that all the 6 billion people in the world in current times would live to 100+ years. And assume that there are no births neither deaths during a study. And all persons would Live in a closed system, from birth to 100 years; i.e. no ins to and no outs from life. 17% of 6.000.000.000 = 1.020.000.000 people - would not be reached by AD in a life-time of 100+ years. 4.980.000.000 people would be attacked Alzheimer’s disease. This is an impressive rate that never could be expressed because millions of old people die every month; and millions of children are born in about the same period, giving origin to more and more old people. Furthermore, most of the elderly die in their seventies or early eighties and there is no time to those enormous rates of AD on 85+, 95+ and 100+ year old people to be expressed. younger people predominate and lower rates enormously This reality OF BIRTHS AND DEATHS; and differences in age of AD manifestation lead to a confusion or incomplete evaluation of statistical results. Clinicians in general assess only the prevalence of AD in comparison with age-matched elderly controls. But it cannot hide that AD doubles every time age increases 5 years in the elderly, after 65 years of age. It cannot mask that AD progresses from no symptoms pathology to harsh or deadly phases. From “clinically” normal people to ruthless cognitive and neuropsychiatric manifestations. This spectrum is very complex and leads to confusion.

  14. 1. SUPPOSITION TO UNVEILING THE REAL INCIDENCE OF ALZHEIMER DISEASE:MOUNT A CLOSED COHORT WITH NO DEATHS UP TO 100 YEARS NO BIRTHS ENTERING SYSTEM IF NOBODY OF THESE 100 ELDERLY INDIVIDUALS (FROM 65-100 YEARS OLD) DIED AND IF NO OTHER SUBJECT ENTERS THE COHORT WE WOULD SEE THAT ABOUT ONLY 20 CENTENARIANS WOULD BE ALZHEIMER’S FREE AND 80 OF THEM WOULD BE ALZHEIMER’S DISEASE CARRIERS. SENILITY OF “ALZHEIMER TYPE” IS NORMAL AGING THESE RESULTS SUGGEST INVERSION OF DIAGNOSIS SENILITY OF “ALZHEIMER FREE TYPE” IS EXCEPTIONAL AGING

  15. 1 Oxidative phosphorylation METABOLISM o2 + ATP glucose Glicolisis TCA (KC) (ETC) Electron transfer chain NORMAL BRAIN AVOIDS PATHOLOGICAL OXIDATION. METABOLISM MUST HAVE BALANCED OXIDATION - ANTIOXIDATION HOMEOSTASIS NEURAL AND GLIAL METABOLIC DYNAMICS AND OXIDATION BUFFERING NITROSATIVE METABOLISM OXIDATIVE METABOLISM RNS ROS Endogenous and exogenous antioxidants act continuously leading to transformation of free radicals and oxidated substrates in electrical neutral substances FREE RADICALS Oxidation buffering declines MITOCHONDRIAL DNA (37 genes Controllingthe ETC Complexes, mRNA, tRNAandrRNAexpression) DAMAGE AND MUTAGENICITY, AS A RESULT OF SLOWLY, CHRONIC STRESSES OF LIFE, DISEAES, UVRs, POISONINGS, CHRONIC depression(?). Transcriptionalcontinuity over life time (?), leads to stochasticerrors. 2 Nuclear (nDNA) DNA damage +mutations ? SYMPTOMLESS OR NORMAL AGING BRAIN ANTIOXIDANT DEFENSES HAVE A MILD DECLINE, INCLINING THE BALANCE TO PROOXIDATION – SENILE DECREASED COGNITIVE, EMOTIONAL AND MOTOR FUNCTIONS. (FEW, UNDETECTED SENILE PLAQUES, NFTs, OTHER MARKERS VERY MILD COGNITIVE DECLINE AGING (SENILITY) Continuous Oxidation and potential damage to enzymes, essential proteins – lipids – DNA – other substrates, transcriptional continuity errors (?)  NEURAL DEATH, ENERGY DECLINE, OS INCREASE INCREASING OXIDATIVE STRESS induced by Aβ senile plaques Neurofibrillary tangles and arteriolar vacuolations ? 3 Environmental and/or genetic factors and adversities (mutations in APP, PS1,PS2, TAU, ApoE4 Gene pression) SYMPTOMATIC AGEING BRAIN : ROBUST DECLINE OF ANTIOXIDANT DEFENSES. PROGRESSIVE BRAIN DYNAMIC IMBALANCE AND FORMATION OF SENILE PLAQUES AND NFTs AS A COMPENSATION RESPONSE TO OXIDATIVE STRESS AND NEUROTOXIC OXIDATION OF NEURONS AND GLIA Amyloid-β cascade Demented Senility Alzheimer type MILD COGNITIVE IMPAIRMENT AGING (SENILITY OR SENESCENCE)

  16. The next 8 slides were taking form this study and are presented To continue the explanation of this proposed experiment Molecular neuropathogenesis of Alzheimer’s disease: an interaction model stressing the central role of oxidative stress. Roberto Rodrigues, Mark A Smith Xinglong Wang, George Perry, Hyoung-gon Lee, Xiongwei Zhu2 & Robert B Petersen* .Future Neurol. (2012) 7(3), 287–305 Interested colleagues could consult free full text

  17. Figure 1 9 Genetic vulnerability: mutant alleles of proteins (tau, AbPP, PS1, PS2, ApoE4, α2MG), enzymes, macromolecules, lipoproteins, Transcriptional errors (?) Serotonin Transporter (5-HTT) short allele lowers threshold to support life adversities (losses, diseases, personal conflicts, catastrophic events, migrations, melancholic personality) 1 2 ? Chronic depression, long-term anxiety, psychosocial stress, inflammation, sepsis, chronic mental and somatic diseases Late Onset Alzheimer’s Disease Serotonin GABA 4 10 3 4 4 Glucose Uptake Cortisol 3 CRF Oxidative Stress, Redox Transition Metals (Fe, Cu), Ab, ApoE4 ‘’Aging Cascade” GR 4 (Cortisol Cascade) 7 4 5 ? NMDAR Hippocampal Neurogenesis (Atrophy-CA3) 7 Glutamate 8-6 ? 8 ? 5 Ca2+ Oxidative Stress ApoEε4, AβPP , Aβ ,Tau 6 ? 6 6 8 Brain Aging Fast Aging ROS - RNS Free Radicals

  18. FIGIGURE 1 – INTERACTIVE NEUROMOLECULAR PATHOGENETIC MODEL OF ALZHEIMER’S DISEASE (WITH CHRONIC MAJOR DEPRESSION- AS AN ILLUSTRATION) 1 – Geneticvulnerability (short allelesofserotonintransporters) may lead to a weak resistance To support life adversities, as severe personal losses, catastrophic events and diseases. 2 – In these vulnerable individuals it may result in chronic major depression, stress and anxiety; and Inflammatory or somatic diseases. 3 – Long term suffering from these depressive and consequent events raises CRF (corticotrophin release factors) which induces the formation of cortisol cascade with consequent elevation of cortisol in the brain. 4 – Corticoid cascade is set with elevation of cortisol in the brain for the reason that it leads to raising glutamate and serotonin; and to reducing GABA levels. Glucocorticoid and mineralocorticoid receptors (GR,MR)concentrations are also stimulated. Glucose uptake also lowers concentration stimulating ROS and RNS and free radicals generation. 5 – Glutamate, particularly, significantly excites N-methyl-D-aspartate receptors (NMDARs) that leads to Intracellular Calcium (Ca2+)strong increasing. 6 –Calcium elevation may elevate ROS (reactive oxygen species) and RNS (reactive nitrogen species). By its turn these reactive species go to free radicals which may result in oxidative stress. 7 – Continuing the cascade: it is possible to ponder that these events may result in hippocampal damage and atrophy, diminishing neurogenesis and synaptogenesis. It is being considered that oxidative Stress may lead by itself to hippocampal atrophy in the cornus-amonis 3 (CA3); and it is probed that Hippocampal atrophy results in CRF elevation, This closes the cycle feeding back the cortisol cascade

  19. Fig 1 continuation Legends from 8 – Contemporary studies show that oxidative stress leads to elevation of amyloid precursor proteins (APP), Amyloid-β ( Aβ) and TAU proteinsas a protectionagainstoxidation. But, traditional studies show thatthesepeptides cause damagetohippocampuscontributingto its atrophyand feeding-back CRF increaseandgoingonintothecorticoidcascade. Furthermore, FreeRadicalsmay inducechronicallytobrainagingandfastaging. 9 – ApoEε4, APP, Aβ, TAU in elevatedlevel; andfast/brainagingmayalsoinduceoxidative stress as manystudies show. Redox transitionmetals (Fe, Cu) are increased leading to the agingcascade, closing the circle. 10 – Genetic vulnerability in the genome to specific proteins (Tau, ApoEε4, Aβ, PS1, PS2), otherenzymes, macromoleculesandlipoproteinsmay cause fragileantioxidantdefensesanddefectsontheproteinconcentration, shapesandsolubilitywithconsequentdeposition. Withagingandtranscriptionalcontinuity many “errors” mayhappen, andfinallyonsetAlzheimer’sdiseasecascademaybe a consequence. Not clear points are aremarkedwith?

  20. Figure 2 4 SYSTEMS DYSHOMEOSTASIS MCI – Alzheimer’s Disease Respiration – O2 H2O Oxidative Phosphorylation 4 1 ANTIOXIDANTS ANTIOXIDANTS +o2 SOD1 1 e- O2 H2O2 OH LOH Fenton Reaction Fe2+ ANTIOXIDANTS Fe3+ Haber-Weiss Redox Cycle GENETIC VULNERABILITY 2 + GENETIC VULNERABILITY Aβ Aβ Macromolecular Complex: Aβ-ApoE4 2 ApoE4 Senile Plaques ApoE4- Fibrillar Aggregation 4 Oligomers (insoluble) ? Monomers (soluble) FIBRILLAR FORM Tau Hyperphosphorylation Neurofibrillary Tangles 3 3 BDNF CHRONIC DEPRESSION GSK-3β NEUROPLASTICITY HIPPOCAMPAL ATROPHY GLUTAMATE + ROS + Ca2+ CORTISOL

  21. Legends from figure 2 1 – Respiration leads to O2 and reduced oxygen to H2O2. Protection from oxidation is made through antioxidants to water. Or, through Fenton reaction that generates hydroxyl radicals and induces Fe²+ change to Fe³+ . Antioxidants avoid severe oxidation from hydroxyl radicals reducing the oxidated Iron through Haber-Weis reaction. 2 - There is a supposition that the Haber-Weiss reaction may oxidize Aβto Aβ+; andApoEε4 issimultaneouslyreducedtoApoEε4. Thismayinducethebuildupof macromolecular complexes andformationof fibrilar andoligomeric Aβpeptidesthateasilydeposits in neurons as senile plaques or neurofibrillary tangles. Furthermore , fibrilar forms may turn on monomers that are soluble. 3 – Chronic depression may lead to neuroplasticity and hippocampal atrophy (fig .1). In genetically vulnerable individuals the system is seriously damaged. 4 – hippocampal atrophy and dyshomeostasis may result also in Alzheimer’s disease in genetically predisposed Individuals.

  22. Figure 3 COOH NH2 A HIS HIS6 Redox Transition Metals Fe3+, Cu2+ HIS13 COOH Apolipoprotein E4 HIS HIS14 Monomeric Aβ HIS Van der Waal Intermolecular dispersion forces Van der Waal Intermolecular dispersion forces Oligomeric Amyloid-β NH2 terminal ASCORBATE MACROMOLECULAR PROTEIN COMPLEX – OLIGOMER Aβ BINDS TO APOE AND REDOX METALS ? (bonds) B + HIS-NH HNHIS Aβ Fe takes an electron from Aβ. Both are stronglymaintainedby Van Der Waaldispersion forces 1 e Van der Waal Intermolecular dispersion or attraction forces Ascorbate 3 Fe2+ Aβ Fe3+ o2 APOLIPOPROTEIN E4 1 H2O2 SOD1 O2 HABER WEISS CYCLE Catalase FENTON REACTION Vitamin E Quenching OH Fe3+ OH ONOO 2 FREE RADICALS o2 Ascorbate-dependent hydroxyl radical OH H2O2 2 GPx DETAILS OF THE MACROMOLECULAR COMPLEX (MMC) DYNAMICS Quenching

  23. Legends from Figure 3 – Interaction among amyloid-beta peptid, Apolipoprotein Eε4. Macromolecular model A An hypothesis of how oligomeric-Aβpeptideisinsolubleandhow it maybebound toApoEε4 and redox transitionmetals (Fe3+ and Cu2+). Thisinteractionmayresult in macromolecular complexes anddepositionofthefibrillarforms in the brain. The connection of monomeric Aβpeptidescouldbedonebyhistidine sites whichmantain alsothebondswithtransitionmetalsandApoEε4. B 1 - Fe3+++ may link to oligomeric Aβbysuppressionofoneelectron; andisreducedto Fe2+ (Haber Weiss cycle). Being a transition metal Fe2+ turnsbytheFentonreaction, to Fe3+. Thismantainsmetalsboundto Aβby Van der Wall dispersion forces. 2 - Thesereactionsgeneratefreeradicals as hydroxylradicalsandothersthatmaydamagecells. Manyantioxidantmoleculesmayholdhomeostasisbyquenchingthefreeradicals. 3 – Histidineboth in AβpeptideandApoEε4, throughtheVan de Waal (HN)forces, maymantaintheadhesionofbothmolecules, This macromolecular dynamics may contributetothelinkageofbothproteinsand redox transitionmetals.

  24. Figure 4 A putative model of how the link of AβandApoEε4 maybemantained ApoE4 ApoE4 ApoE4 ApoE3 + ApoE2 ApoE3 + ApoE2 ApoE3 + ApoE2 (A constant to be determined, that means the homeostasis of the system) -k -k -k = = = The “OFF” phase: Aβ in normal level ApoE4 increases, as there are enough Aβ monomers to form the soluble macromolecular complex with it. This phase is limited and critical; otherwise, oligomeric Aβ may aggregate, losing its solubility. Aβ The “ON” phase: Aβ burden In this phase ApoE4 decreases the binding to Aβ and alleviates the macromolecular complex burden and Aβ deposition, with increased solubility, may be easily exported from the neurons. A tendency to maintain homeostasis = Aβ -K is an optional tool. It may be any other constants. The important is the representation of the homeostasis necessary for the molecular dynamics in normality. It expressed negative correlation.

  25. Next two slides were taken from this study Still not published. It explains the genomic Vulnerability of MDD and AD and the interaction with environmental help that may be supplied by the antioxidant and other supplements in this experiment GENOMIC VULNERABILITY IS THE ONLY DIFFERENCE BETWEEN THE OXIDATIVE STRESS INDUCED MAJOR DEPRESSIVE DISORDER AND ALZHEIMER’S DISEASE SPECTRA Roberto Rodrigues, George Perry, and R.Petersen (waiting forapproval to go on press)

  26. PSS – STLE - MASDs Fig. 1 - ILUSTRATION OF MDD AND AD SPECTRA CASCADES. EXPLANATIONS IN TEXT. DC GVD HPA – AVP - HPG MASD – mental/affective somatic diseases. PSS – Psychosocial stress. SLTE – severe life threatening events. BDC – brain defense molecular cascades CKI – cytokine and inflammatory cascades OS – OXIDATIVE STRESS GCC – glucocorticoid cascades GVD – genomic vulnerability to depression GVAD – genomic vulnerability to Alzheimer disease DC - depression cascade ADC – Alzheimer disease cascade AD – Alzheimer disease MDD – major depressive disorder BDMC – brain defense molecular cascades ODC HA MDD OXIDATIVE STRESS CK - INFL ADC GVAD AD AODs Aβ – TH – ApoEε4

  27. Fig 2 – ILLUSTRATION OF THE MDD and AD CASCADES –CONCLUSIONS: EXPLANATION IN TEXT: MDD – major depressive disorder, AD – Alzheimer’s disease, PSS – psychosocial stress, MASD – mental, affective and somatic diseases, SLTE – severe life threatening stress, BOMD – brain oxidation molecular defenses, GCC – glucocorticoid cascades, ODC – “oxidopamatergic” cascade, GTHC – gonadotropin hormones cascade, DC – depression cascade, ADC – Alzheimer’s disease cascade, OS – oxidative stress, GVD – genomic vulnerability to depression, GVAD – genomic vulnerability to AD. PSS MASD SLTE MDD AD BOMD CKIC ODC GCC-GTHC GVAD OS GVD ADC DC OS

  28. G. ALI QURESHI OXIDATIVE STRESS AND NEURODEGENERATIVE DISORDERS. Some supporter studies from S. HASSAN PARVEZ Chapter 9 Down Syndrome, Antioxidant Balance and the “Gene DosageEffect” Hypothesis 219. J.B. de Haan, P.J. Crack, M.A. Pritchard, and I. Kola. Chapter 12 The Key Role of Oxidative Stress in Alzheimer’s Disease 267Paula I. Moreira, Akihiko Nunomura, Kazuhiro Honda, GjumrakchAliev,GemmaCasadesus, Xiongwei Zhu, Mark A. Smith, and George Perry Chapter 20 Prospects for Antioxidant Therapy in Mild Cognitive Impairment and Alzheimer’s Disease 451 Akihiko Nunomura, George Perry, and Mark A. Smith Chapter 31 Oxidative Stress in Phagocytic Cells: Changes with Age and Effect of Melatonin 737. C. Barriga, M.P. Terrón, S.H. Parvez, J. Cubero, D. Narciso, S.D. Paredes, S. Sánchez, and A.B. Rodríguez Chapter 23 Diet, Herbs, and Nutritional Protection against Oxidative Stress in Neurological Diseases 525. Carlos KusanoBucalenFerrari. Chapter 25 Green and Black Tea in Brain Protection 581 JustynaOstrowska, WojciechŁuczaj, AgnieszkaAugustyniak, and El˙zbietaSkrzydlewska Chapter 27 Prevention and Therapy of Neurodegenerative Disorders: Role of Nutritional Antioxidants 621 Vincenzo Di Matteo, Massimo Pierucci, Giuseppe Di Giovanni, and EnnioEsposito

  29. LESTER PACKER, PH.D. ENRIQUE CADENAS, M.D., H.D. Chapter 3 Ginkgo biloba Extract and Alzheimer’s Disease: Is the Neuroprotection Explained Merely by the Antioxidant Action? ...43Monica Garcia-Alloza, Sarah A. Dodwell, and Brian J. Bacska Chapter 22 Age-Related Neuronal and Behavioral Deficits are Improved by Polyphenol-Rich Blueberry Supplementation 373 Francis C. Lau, Barbara Shukitt-Hale, and James A. Joseph Chapter 4 Mitochondrial Nutrients: Reducing Mitochondrial Decay to Delay or Treat Cognitive Dysfunction, Alzheimer’s Disease, and Parkinson’s Disease. 59. Yves Christen Chapter 24 Nutrition, Brain Aging, and Alzheimer’s Disease 409 YafeiZhang and Rena Li Chapter 26 Nutriproteomics Approach to Understanding Dementia-Relevant Brain Protein Changes in Response to Grape Seed Extract, a Dietary Antioxidant...457 Helen Kim, Shannon Eliuk, JessyDeshane, Stephen Barnes, and SreelathaMeleth Chapter 6 Amyloid-β and τ in Alzheimer’s Disease: What is the Neuropathology Trying to Tell Us?121 Rudy J. Castellani, Akihiko Nunomura, Hyoung-gon Lee, Xiongwei Zhu, George Perry, and Mark A. Smith PROJECT ORIENTATION Chapter 7 Antioxidant Therapies in the Prevention and Treatment of Alzheimer Disease. 131 Paula I. Moreira, Xiongwei Zhu, Akihiko Nunomura, Mark A. Smith, and George Perry 10 Oxidative Stress and Neurodegeneration: An Inevitable Consequence of Aging? Implications for Therapy . . . . . . . . . . 305 Roberto Rodrigues, David J. Bonda, George Perry, Rudy J. Castellani, Gemma Casadesus, Hyoung-gon Lee, Hyun-Pil Lee, Xinglong Wang, Xiongwei Zhu, Robert B. Petersen, and Mark A. Smith. (Michael S. Ritsner Editor Brain Protectionin Schizophrenia, Mood and Cognitive Disorders). Chapter 13 Green Tea and Resveratrol as Protective Agents against Neurotoxins. 225 StéphaneBastianetto, Han Ying-Shan, and QuirionRémi Chapter 15 Apple Phenolics and Alzheimer’s Disease. 247 Ho Jin Heo, Dae-Ok Kim, and Chang Yong Lee Molecular neuropathogenesisof Alzheimer’s disease: an interaction model stressing the central role of oxidative stress. Roberto Rodrigues, Mark A Smith Xinglong Wang, George Perry, Hyoung-gon Lee, Xiongwei Zhu2 & Robert B Petersen* .Future Neurol. (2012) 7(3), 287–305 Chapter 17 The Essentiality of Iron Chelation in Neuroprotection: A Potential Role of Green Tea Catechins..277 Silvia A. Mandel, Tamar Amit, HailinZheng, OrlyWeinreb, and MoussaB.H. Youdim. GENOMIC VULNERABILITY IS THE ONLY DIFFERENCE BETWEEN THE OXIDATIVE STRESS INDUCED MAJOR DEPRESSIVE DISORDER AND ALZHEIMER’S DISEASE SPECTRA Roberto Rodrigues MD, PhD, George Perry, and R.Petersen (waiting approval) Chapter 18 Ginkgo biloba Extract EGb 761 Extends Life Span and Attenuates H2O2 Levels in a Caenorhabditiselegans Model of Alzheimer’s Disease..301 Julie V. Smith and Yuan Luo

  30. SUMMARY DESCRIPTION OF THE MAIN ANTIOXIDANTS METAL /RADICAL SCAVENGERS, GENE SUPPORTERS, MITOCHONDRIA PROTECTORS, AND OTHER ESSENTIAL VITAMINS AND SUPPLEMENTS WHICH MAY PREVEN AND/OR DELAY COGNITIVE IMPARIMENT, AGING AND ALZHEIMER’S DISEASE. SOME OF THEM MAY BE USED WITH SIMULTANEUOUS ADMINISTRATION FOR 2 - 4 YEARS.

  31. Antioxidants, chelating agents, molecular repairing and enzyme stimulators/inhibitors supplements, Mitochondria protectors and suppliers VITAMINS OF THE COMPLEX B RESVERATROL (GRAPE FRUIT SEED and SKIN - WINE) GINGKO BILOBA EPI-GALLO-CATECHINS GALLATE (GREEN TEA) ASCORBATE (VITAMIN C) TOCOPHEROL (VITAMIN E) EICOSOPENTANOIC ACID – EPA DOCOSOHEXANOIC ACID - DHA CURCUMIN (CURCUMA LONGA) CREATINE Thiamine (B1): Riboflavin (B2) Niacin (B3) Pantothenate (B5) Pyridoxine (B6) Biotin (B7) FolicAcid Vitamin B12 COENZYME Q10 α-LIPOIC /DIHYDROLIPOIC ACID MELATONIN OTHER ANTIOXIDANT VITAMINS VITAMIN C (ASCORBATE) VITAMIN E (TOCOPHEROLS) VITAMIN A (CAROTENOIDS)

  32. GREEN TEA: EPI-GALLO-CATECHINE GALLATE • EGCGIS A POTENT REMODELING AGENT OF MATURE AMYLOID FIBRILS. • The polyphenol (-)-epi-gallocatechin • gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis Promotes the self-assembly of unfolded proteins (unstructured oligomers) – converts α-synucleins andβ-amyloidfibrils in non toxicpeptideaggregates • Directly binds to β-sheet rich aggregates . • Mediates the conformational change into • monomers or small diffusible oligomers. Green tea catechins have been reported to possess various physiological and pharmacological properties, including effective antioxidants that scavenge free radicals Jan Bieschke1, Jenny Russ et al. Taken From: EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity 7710–7715 ∣ PNAS ∣ April 27, 2010 ∣ vol. 107 ∣ no. 17

  33. Intensely studied due to its high antioxidant activity Presence in preventive amounts in green tea Green tea is one of the Nutrients most used in The world for more than 3000 years, when it was considered a therapeutic Agent as curcumin in the Middle and Far East World Green tea’s preventive effects are stronger with a mixture of tea catechins, or green tea extracts than with EGCG alone FLAVONOIDS EPI-GALLO CATECHIN GALLATE(EGCG) Green tea extract administration significantly increases the activity of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) Zhang et al. Green tea polyphenol epigallocatechin-3-gallate inhibits oxidative damage and preventive effects on carbon tetrachloride-induced hepatic fibrosis. The Journal of Nutritional Biochemistry, 18 (2007), pp. 795–805.

  34. ENERGY METABOLISM NEUROPLASTICITY PREVENTS THE ONSET OF ALZHEIMER’S DISEASE GINGKO BILOBA PLURY FUNCTIONAL INTERACTION GINGKO BILOBA Egb 761 REDUCTION IN PRODUCTION, OLIGOMERIZATI0N AND TOXICITY OF Aβ PEPTIDE A SERIES OF MOLECULAR SIGNALING, MANY OF THEM YET UNCLEARED, CHARACTERIZES THE MULTY COMPLEX FUNCTIONAL ACTIONS OF GINGKO BILOBA FREE RADICAL SCAVENGER MEMBRANE RECEPTORS ACTION REGULATING CELLULAR GENE EXPRESSION. EXTREMELY LOW PARA EFFECTS There is a unique interdependency between actions of the various constituents of EGb761

  35. Recent research ABOUT EGb 761 reveals that: GINGKO BILOBA HAS AN EXCELLENT NEUROPROTECTIVE FUNCTION IN DEMENTIA 1 – IMPROVES memory, cognition, orientation, abilities 2 – PROMOTES recovering of neuropsychiatric symptoms 3 – INCREASES quality of life 4 - STIMULATES normal activities of daily life 5 – THE EFFECTS are strong and detectable by caregivers. EGb 761 may be combined with donepezil or other acetylcholinesterases In this condition its anti-dementia qualities increases in relation to controls or with its exclusive administration. In prevention it may be used in dosages 80 mg – 240 mg daly No important safety concerns. Actions may equal memantine

  36. Tumeric Curcuma longa – curcumin is a strong antioxidant and metal scavenger Curcumin has impressive antioxidant, chemopreventive, chemotherapeutic, and chemosensitizing activities (Laura S. Angelo and Razelle Kurzrock, Clinical Cancer Res 2009;1123 15(4) February 15, 2009) Turmeric and Green Tea: A Recipe for the Treatment of B-Chronic Lymphocytic Leukemia.55 Commentary on Ghoshet al., p.1250 RECENT REPORTS CURCUMIN AS ANTI-ALZHEIMER’S DISEASE TRANSGENIC MICE STUDIES Reducesoxidativedamageand Amyloidpathology Antiinflammatory AlternativetoNSAIDs Low doses decrease plaque Burdenandinsolubleamyloid In 40% to 50% in AD. Lowersoxydizedproteins Andproinflammatorycytokines DECREASES FIBRIL AND OLIGOMER FORMATION LOW TOXICITY: THIS INDIAN SPICE COMPONENT HAS PROMISE FOR PREVENTION OF AD

  37. Curcumin acts particularly on oxidative damage preventing neurons and synaptic destruction through Intracellular aggregates. Its action prevents cholesterol increasing and contributing to amyloid and Aβ-peptide oligomers and fibrils to delay deposition. It is also antiinflammatory agent; and contributes to Amyloid clearance. All these interacted neuromolecular signaling protection constitute a very strong anti-Alzheimer’s agent.

  38. Mentioned author about curcumin: astonishing benefic properties in AD and many other illnesses

  39. Resveratrol – the red wine flavonoid Low concentration of resveratrol protects and prevents INDUCES BRAIN NEUROGENESIS AND CARDIOVASCULAR HOMEOSTASIS CARDIOVAASCULAR HOMEOSTASIS Atherosclerosis Arterial Hypertension Ischemic reperfusion Vascular dementia Neurodegeneration: Alzheimer’s disease Diabetes, obesity, tumors NNONO SYNTHASE DIADIA DIABETES PLATELET AGGREGATION NEURODEGENERATIVE DISEASES INTER-LEUCINES 3,1 PUBLICATIONS ABOUT RESVERATROL More than 10.000 in the last 15 years ---- Most of them report medium to high benefits About 40% - Wait future researches About 20% - Do negate any profits TUMORS LDL OXIDATION ROS - NRS HYPERTENSION Used for more than 4000 years Also as a drink of Gods

  40. Resveratrol • 1 – may be given in capsules to avoid the risk of wine dependency 2 – Many studies report a low bioavailability • 3 – It’s very ample range of effects and systems protection in the is a positive quality for use over long time in Prevention of Alzheimer’s, Parkinson’s diseases, and other dementias. • 4 – Many of the cardiovascular, metabolic, homeostatic, hematologic, Immunologic, anti-inflammatory, anti-diabetic and anti-lipidemiceffects have an indirect anti-dementia prevention over a long time administration

  41. FISH OIL : ω-3 (omega 3) Transcription (10-fold) of transthyretin (TTR) DOCOSOHESANOIC ACID - DHA TTR – a β-amyloid protein scavenger prevents amyloid aggregate formation (like Ginkgo Biloba) Particularly useful in Preventing CVDs, stroke, Alzheimer’s disease, Vascular dementia Fish oil (27% DHA) • Fish oil feeding alters genes in the neurons of the hippocampus. EICOSOPENTANOIC ACID - EPA • Drastic arachidonic acid reduction from the • Phosphatidylinositols Many other properties still in study -

  42. COENZYME Q-3: COMPONENT OF ELECTRON TRANSPORT CHAIN (ETC) IN MITOCHONDRIA ATP PRODUCTION COENZYME Q-10, when there is depletion, leads to apoptotic and necrotic neuron death DEFICIENCY function in mitochondria GABA neurons death COENZYME Q-10 NORMAL FUNCTION in mitochondrial ETC Electron transference: complex I/II to III Avoids neurodegenerative damage (Alzheimer’s disease , ataxia, others) INHIBITSproduction of ROS • Coenzyme Q10: essential cofactor of the ETC oxidative stress • two hallmarks • of mitochondrial dysfunction/ • Q10: a Potent free radical • scavenger in lipid and mitochondrial membranes energy depletion • In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in • cerebral cortex mitochondrial concentrations of coenzyme Q10.

  43. melatonin MOVES JUST THE FREE RADICAL ENZYMATIC DEFENSES AGAINST OXIDATIVE STRESS, THE EARLIEST PHYSIO PATHOGENETIC ETIOLOGY ON NEURODEGENERATIVE ILLNESSES, PARTICULARLY AD (DEPRESSION ALSO?) IMPORTANT AND INTERESTING ASPECTS: IN ALZHEIMER’S DISEASE PROTECTION: REGULATES CIRCADIAN RHYTHM HOMEOSTASIS FOR 24 HOURS REGULATES SLEEP WITHOUT THE USE OF BENZODIAZEPINES IS ONCOSTATIC (MAY BE INDUCES PCD IN THE BRAIN? ) • Al these functions may indirectly help AD protection (?) CORRELATES POSITIVELY WITH THE BLOOD ANTIOXIDANT LEVEL CROSSES EASELY THE BBB, INCLUDING MITOCHONDRIA MELATONIN IN EITHER ENDOGENOUS OUR PHARMACOLOGICAL MEANS • Induces enzymatic • Actions to remove • Free radicals through glutathione peroxidase, superoxide dismutase, catalase Inhibits peroxidative enzyme • nitric oxide synthase.

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