Alzheimer’s Disease Causation and Sequence of Events: The Hidden, Cumulative, Exponentiated Ingredient Inherent in the Degradation Cascade

Alzheimer’s Disease Causation and Sequence of Events: The Hidden, Cumulative, Exponentiated Ingredient Inherent in the Degradation Cascade This document was created for cSMARTcorp through Life Science TherapyPfizer and Johnson & Johnson recently concluded and announced on July 23rd, 2012 resultsof Phase 3 of the clinical trial on a jointly developed drug bapineuzumab. The closelywatched experimental treatment for Alzheimer’s disease proved ineffective in its first largeclinical trial. This utter failure completely debunked a theory about the cause of the disease.The drug is an antibody designed to bind to beta-amyloid, a protein that has toxic effects inthe brain and is believed by many scientists to be a cause of Alzheimer’s.The drug bapineuzumab, did not improve either cognition or daily functioning of patients,the intended endpoints, compared to a placebo in the Phase 3 trial. One of the principalinvestigators in the study, Dr. Reisa Sperling, stated “there was no sign of any effect.”Moreover, the patients in the new trial — 1,100 Americans with mild to moderate disease —all had a gene called ApoE4, which raises the risk a person will get Alzheimer’s disease andcan make the disease worse.Bapineuzumab is the latest of several drugs aimed at clearing beta amyloid or preventing itsformation that have failed to work in clinical trials. The failures have finally raised questionsabout whether beta amyloid really is the cause of Alzheimer’s disease or is beta amyloidactually the symptom of Alzheimer’s disease. Trauma or injury is an example of treating thesymptom rather than the cause. Suppose you are riding your bike and are involved in acollision with a car. You are taken to the hospital and x-rays reveal multiply compounddisplaced fractures. The attending physician prescribes only morphine for the pain andreleases you. Insane, right! He treated the symptom of pain not the cause of the pain whichis multiply compound displaced fractures. The following article completed in 2009 elucidatesour theory on the etiology of this disease after decades of combined research and practicalclinical application. The present article examines several lines of converging evidence suggesting that the slow and insidious brain changes that accumulate over the lifespan, resulting in both natural cognitive aging and Alzheimers disease (AD), represent a metabolism reduction program. A number of such adaptive programs are known to accompany aging and are thought to have decreased energy requirements for ancestral hunter-gatherers in their 30s, 40s and 50s. Foraging ability in modern hunter-gatherers declines rapidly, more than a decade before the average terminal age of 55 years. Given this, the human brain would have been a tremendous metabolic liability that must have been advantageously tempered by the early cellular and molecular changes of AD which begin to accumulate in all humans during early adulthood. Before the recent lengthening of life span, individuals in the ancestral environment died well before this metabolism reduction program resulted in clinical AD, thus there was never any selective pressure to keep adaptive changes from progressing to a maladaptive extent. Aging foragers may not

have needed the same cognitive capacities as their younger counterparts because of thebenefits of accumulated learning and life experience. It is known that during bothchildhood and adulthood metabolic rate in the brain decreases linearly with age. Thistrend is thought to reflect the fact that children have more to learn. AD "pathology" maybe a natural continuation of this trend. It is characterized by decreasing cerebralmetabolism, selective elimination of synapses and reliance on accumulating knowledge(especially implicit and procedural) over raw brain power (working memory). Overdecades of subsistence, the behaviors of aging foragers became routinized, their motormovements automated and their expertise ingrained to a point where they no longernecessitated the first-rate working memory they possessed when younger and learningactively. Alzheimer changes selectively and precisely mediate an adaptation to thismajor life-history transition. AD symptomatology shares close similarities withdeprivation syndromes in other animals including the starvation response. Bothmolecular and anatomical features of AD imitate brain changes that have beenconceptualized as adaptive responses to low food availability in mammals and birds.Alzheimers patients are known to express low overall metabolic rates and aregenetically inclined to exhibit physiologically thrifty traits widely thought to allowmammals to subsist under conditions of nutritional scarcity. Additionally, AD isexamined here in the contexts of anthropology, comparative neuroscience, evolutionarymedicine, expertise, gerontology, neural Darwinism, neuroecology and the thriftygenotype.Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by twohallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century agothese hallmark lesions were purified and their protein constituents identified, precipitatingan avalanche of molecular studies as well as substantial optimism about successfultherapeutic intervention. In 2010, we now have copious knowledge on the biochemicalcascades that produce these proteins, the different modifications and forms in whichthese proteins exist, and the ability to selectively target these proteins for therapeuticintervention on an experimental basis. At the same time, there has been no discerniblealteration in the natural course of AD in humans. While it may be that the complexity ofAD will exceed our capacity to make significant treatment progress for decades or more, aparadigm shift from the reductionism that defines amyloid-? and tau hypotheses, to onethat more accurately reflects the meaning of neuropathological changes, may bewarranted. We have demonstrated that AD pathology is a manifestation of cellularadaptation, specifically as a defense against oxidative injury and nutrient deprivation. Assuch, AD pathology is therefore a host response rather than a manifestation of cytotoxicprotein injury, and is unlikely to be a fruitful target for therapeutic intervention. An“expansionist” view of the disease, we believe, with oxidative stress and nutrientdeprivation as manifestations of the pleiotropic and upstream process, more aptlydescribes the relationship between various and numerous molecular alterations andclinical disease.Contrary to common concepts, the brain in Alzheimers disease (AD) does not follow asuicide but a rescue program. Widely shared features of metabolism in starvation,hibernation and various conditions of energy deprivation, e.g. ischemia, allow the

definition of a deprivation syndrome which is a phylogenetically conserved adaptiveresponse to energetic stress. It is characterized by hypometabolism, oxidative stress andadjustments of the glucose- fatty acid cycle. Cumulative evidence suggests that the brainin aging and AD actively adapts to the progressive fuel deprivation. The counterregulatorymechanisms aim to preserve glucose for anabolic needs and promote the oxidativeutilization of ketone bodies. The agent mediating the metabolic switch is soluble Abetawhich inhibits glucose utilization and stimulates ketone body utilization at various levels.These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the keytransmitter and effector systems regulating glucose metabolism. Hormonal and effectorsystems which promote ketone body utilization, such as glucocorticosteroid and galaninactivity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketonebody metabolizing enzymes, are enhanced. A multitude of risk factors feed into thispathophysiological cascade at a variety of levels. Taking into account its pleiotropicregulatory actions in the deprivation response, a new name for Abeta is suggested:deprivin. On the other hand, cumulative evidence, taken together compelling, suggeststhat senile plaques are the dump rather than the driving force of AD. Moreover, theneurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contributesignificantly to the in vivo pathophysiological events. This archaic program, conservedfrom bacteria to man, aims to ensure the survival of a deprived organism and controlssuch divergent processes as sporulation, hibernation, aging and aging-related diseases. Incontrast to the immature brain, ketone body utilization of the aged brain is no longersufficient to meet the energetic demands and is later supplemented by lactate, thusrecapitulating in reverse order the sequential fuel utilization of the immature brain. Thetransduction pathways which operate to switch metabolism also convey the programmingand balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompassesthe reiteration of developmental processes such as transcription factor activation, tauhyperphosphorylation, and establishment of growth factor independence by means ofCa2+ set point shift. Thus, the increasing energetic insufficiency results in the progressivecentralization of metabolic activity to the neuronal soma, leading to pruning of theaxonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticityand, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration ofvulnerable neurons. Finally, it is outlined that genetic (e.g. Downs syndrome, APP andpresenilin mutations and apoE4) and environmental risk factors represent progeroidfactors which accelerate the aging process and precipitate the manifestation of AD as aprogeroid systemic disease. Aging and AD are related to each other by thresholdphenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion,of a metabolic stress response. Specific implicates to directly addressing the nutritionaldeficiency and cellular starvation therefore, need to be incolcated by the very early onsetof Stage IV to have a rescue or resusciative success opportunity. This time-basedscenario, is substantively based on the rate of ABETA buildup relative to the degree ofnutrient deprivation. The ensuing model directly implies that up to and including the onsetof the quartenary phase of the disease state, that 50% of the neuronal energy and neuralcells are still intact and quite capable of salvaging. Transcription and translation factorsare still operant and cellular turnover, though truncated, are still viable, nutritional

protocols must be incorporated at this point immediately to offset thedeprivation/starvation cascade from proceeding any further.Folate deficiency has been associated with age-related neurodegeneration. One directconsequence of folate deficiency is a decline in the major methyl donor, S-adenosylmethionine (SAM). The dietary deficiency in folate and vitamin E, coupled pro-oxidantstress induced by dietary iron, increases presenilin-1 expression, gamma-secretaseactivity, and Abeta levels in normal adult mice. These specific increases are potentiated byapolipoprotein E deficiency as shown by treatment of transgenic mice homozygouslylacking murine apolipoprotein E. Dietary supplementation with SAM in the absence offolate attenuated or alleviated these deleterious consequences. These findings linknutritional and genetic risk factors for age-related neurodegeneration and underscore thatdietary supplementation with SAM may be useful to augment therapeutic approaches.Hyperphosphorylated tau is the major component of paired helical filaments inneurofibrillary tangles found in Alzheimers disease brains, and tau hyperphosphorylationis thought to be a critical event in the pathogenesis of this disease. The objective of ourinvestigation is to take the reproduction of tau hyperphosphorylation in human/animalmodels accomplished by inducing hypoglycemia and correlate this to our nutrientdeprivation model. For example, food/nutrient deprivation of mice for 1 to 3 daysprogressively enhanced tau hyperphosphorylation in the hippocampus, to a lesser extentin the cerebral cortex, but the effect was least in the cerebellum, in correspondence withthe regional selectivity of tauopathy in Alzheimers disease. This hyperphosphorylation isreversible by refeeding for 1 day. We intend to further elucidate this nutrient deprivationparadigm and better understand the mechanisms of this phenomenon, and propose thisas a simple model to study in vivo tau phosphorylation and dephosphorylation which arealtered in Alzheimers disease as a corollary of our nutrient deprivation model ofAlzheimers disease.1 HPA Regulation of Cortisol SecretionThe secretion of cortisol via HPA regulation was assumed to be in a"steady- state" and represented using a standard "Michaelis-Menten" typebiochemical equations and rate equations (Eq 1–3).(1)

(2)(3)2 Cortisols Interaction with MR and GR ReceptorsThe binding of cortisol to CA1 MR receptors was representedusing the Hill equation for ligand/receptor binding. The first halfof the ordinary differential equation (ODE) represents thegeneration of MR activity, while the second half of the ODE is adegradation reaction, which is necessary to ensure that MRactivity does not rise indefinitely (Eq 4).(4)The binding of cortisol to GR CA1 hippocampal neurons wasexpressed also using the Hill equation, and combined with adegradation reaction similar to Eq 4, to ensure that GR receptoractivity does not rise indefinitely (Eq 5).

(5)3 Aging of CA1 neurons and cortisol stimulationThe population of neurons in the CA1 region of thehippocampus was defined by combining the stimulation of theneuronal population by neuronal growth factors and MR activity,with the last part of the equation representing the ageingrelated death of neurons (Eq 6).(6)A rate constant for the decline of neuronal growth factors with time wasalso included (Eq 7).(7)4 Excitatory Input SynapsesExitatory input synapses (Ue) were defined with reference to therelationship between the neuronal population and excitatory impulses withdegradation of neuronal arborisation (Eq 8).

(8)It was assumed that the numbers of excitatory synapses would be relatedboth to the numbers of neuronal branches (dendrites) and also synapticexcitatory signals (Eq 9). (9)5 Inhibitory Input SynapsesInhibitory synapses (Ui) were defined by combining the activation of GRreceptors with the degradation of synaptic inhibitory signals (Eq 10). (10)6 Aging related changes in Synaptic Current [Is]Synaptic current was defined as the net combination of excitatory andinhibitory input synapses (Eq 11). (11)

7 Synaptic OutputSynaptic output (Vs) was defined as a combination of synaptic output witha decline of synaptic output related to time (Eq 12). (12)8 Hippocampal AtrophyIn the model hippocampus atrophy was defined using an SBML rule whichwas implemented in MathSBML as detailed below.(13)9 Hippocampal Tissue OutputThe first half of the equation represented the generation of hippocampusoutput (HO), while the second half of the equation represented thedegradation of hippocampus output. The degradation of HO had nobiological significance, but served to ensure that hippocampus output didnot rise indefinitely when simulations were conducted but instead reacheda steady state (Eq 14). (14)Firstly the system model was brought into a steady state, and the initialhippocampus output was set at 100% which is a mathematical

representation of activity, and does not refer to the cognitive ability of thein silicoindividual modelled in this paper.The response to stress was examined by using events in SBML designedto mirror physiological responses to stress. The first event triggered anincrease in the reaction rate kcrh, which raised the secretion of CRH. This inturn precipitated an increase in ACTH, followed by an increase inplasma cortisol. The second event returned kcrh to its original valueafter a short period of time which produced a yearly increase incortisol. Kcr was not returned to its original value after each event inorder so as to represent stress and ageing altering the ability of theHPA-axis to recover from repeated challenges which reflects the clinicalhypothesis that ageing impairs homeostatic adaptations of cortisolsecretion to stressREFERENCES:Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A,Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patientswith Parkinsons disease. Histol Histopathol 12:25–31.Barber AJ, Nakamura M, Wolpert EB, Reiter CE, Seigel GM, Antonetti DA, Gardner TW(2001) Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism thatreduces the activation of caspase-3. J Biol Chem 276:32814–32821.Berg TO, Fengsrud M, Strømhaug PE, Berg T, Seglen PO (1998) Isolation andcharacterization of rat liver amphisomes. Evidence for fusion of autophagosomes withboth early and late endosomes. J Biol Chem 273:21883–21892.Bi X, Zhou J, Lynch G (1999) Lysosomal protease inhibitors induce meganeurites andtangle-like structures in entorhinohippocampal regions vulnerable to Alzheimers disease.Exp Neurol 158:312–327.Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ (1995)Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rathepatocytes. J Biol Chem 270:2320–2326.Boellaard JW, Schlote W, Tateishi J (1989) Neuronal autophagy in experimentalCreutzfeldt-Jakobs disease. Acta Neuropathol (Berl)78:410–418.Boland B, Nixon RA (2006) Neuronal macroautophagy: from development todegeneration. Mol Aspects Med 27:503–519.

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Alzheimer’s Disease Causation and Sequence of Events: The Hidden, Cumulative, Exponentiated Ingredient Inherent in the Degradation Cascade

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Alzheimer’s Disease Causation and Sequence of Events: The Hidden, Cumulative, Exponentiated Ingredient Inherent in the Degradation Cascade Document Transcript

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