THE BETA-AMYLOID PATHWAY IN ALZHEIMER'S DISEASE

By JOSHUA THOMAS

CONTENTS BETA-AMYLOID AS TARGET CHAPTER THE AMYLOID HYPOTHESIS OF ALZHEIMER’S DISEASE AND PROSPECTS FOR THERAPEUTICS A BRIEF HISTORY OF ALZHEIMER’S DISEASE APP PROCESSING AND THE AMYLOID HYPOTHESIS PRESENT AND FUTURE ALZHEIMER THERAPEUTICS B-SECRETASE AND INHIBITORS G-SECRETASE, INHIBITORS AND MODULATORS A-SECRETASE AND MODULATORS INHIBITORS OF CHOLESTEROL BIOSYNTHESIS AMYLOID AGGREGATION INHIBITORS IMMUNOLOGICAL APPROACHES PERSPECTIVE REFERENCES CHAPTER TARGETING ALZHEIMER’S G-SECRETASE: GENETIC AND CHEMICAL MODULATION G-SECRETASE: THE KEY ENZYME FOR THE GENERATION OF AMYLOID B PROTEIN PS1 CARRIES THE ACTIVE SITE OF THE G-SECRETASE G-SECRETASE COMPLEX IS COMPOSED OF FOUR COMPONENTS G-SECRETASE CLEAVES MULTIPLE SUBSTRATES, INCLUDING APP AND NOTCH CHEMICAL MODULATION OF G-SECRETASE ACTIVITY TARGETING G-SECRETASE IN ZEBRA?SH TARGETING G-SECRETASE IN RODENTS TARGETING G-SECRETASE IN HUMANS MECHANISMS OF CHEMICAL MODULATION OF G-SECRETASE ACTIVITY BINDING OF G-SECRETASE INHIBITORS TO THE ACTIVE SITE BINDING OF G-SECRETASE INHIBITORS TO THE DOCKING SITE BINDING OF G-SECRETASE MODULATOR TO THE SUBSTRATE PATHWAYS INDEPENDENT OF THE G-SECRETASE COMPLEX GENETIC MODULATION OF G-SECRETASE ACTIVITY BY FOUR COMPONENTS PRESENILIN NICASTRIN THE G-SECRETASE COFACTOR CONCLUSION ACKNOWLEDGEMENTS CHOLESTEROL AND ALZHEIMER’S DISEASE: THE MOLECULES, THE TARGETS INTRODUCTION ALZHEIMER’S DISEASE: CONTRIBUTION OF THE CENTRAL NERVOUS SYSTEM AND PERIPHERAL DEFECTS APOLIPOPROTEIN E: THE FIRST LINK WITH CHOLESTEROL LOW-DENSITY LIPOPROTEIN RECEPTOR (LDLR) FAMILY: THE UPTAKE OF CHOLESTEROL ACYL-COENZYME A CHOLESTEROL ACYLTRANSFERASE (ACAT): THE INTRACELLULAR DISTRIBUTION OF CHOLESTEROL HMG-COA: THE RATE-LIMITING STEP OF CHOLESTEROL SYNTHESIS SELADIN 1: THE LAST STEP OF CHOLESTEROL SYNTHESIS CHOLESTEROL 24-HYDROXYLASE (CYP46) AND THE ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1): THE REMOVAL OF CHOLESTEROL 24-HYDROXYCHOLESTEROL (24-OHC) AND 27-HYDROXY- CHOLESTEROL (27-OHC): THE METABOLITES OF CHOLESTEROL CONCLUDING REMARKS THE BIMODAL FEATURES OF BUTYRYLCHOLINESTERASE IN CHOLINERGIC NEUROTRANSMISSION AND AMYLOID SUPPRESSION AMYLOIDOSIS NEURODEGENERATION AND AD AMYLOID BETA PRODUCTION AND ACCUMULATION AMYLOID BETA NATURAL DEGRADATION AND CLEARANCE TREATMENT AND PHARMACOLOGICAL INTERVENTIONS IN AD ANTICHOLINESTERASE THERAPIES ANTIAMYLOID THERAPIES CHOLINESTERASES PHYSIOLOGICAL ROLES OF CHOLINESTERASES THE INVOLVEMENT OF CHOLINESTERASES IN AD BUTYRYLCHOLINESTERASE AS AN AD MODULATOR POSITION 541 OF BUTYRYLCHOLINESTERASE POSITION 539 OF BUTYRYLCHOLINESTERASE DISCUSSION AND PERSPECTIVES ACKNOWLEDGMENTS SCYLLO-INOSITOL: A POTENTIAL THERAPEUTIC FOR ALZHEIMER’S DISEASE THE INOSITOL STEREOISOMERS SCYLLO-INOSITOL IN NATURE INOSITOL SYNTHESIS AND DEGRADATION PATHWAYS THE INOSITOL TRANSPORTERS H(+)-MYO-INOSITOL TRANSPORTER NA(+)-MYO-INOSITOL TRANSPORTER INOSITOL E?UX INOSITOL POOLS INOSITOL INCORPORATION INTO PHOSPHATIDYLINOSITOL INOSITOL IN HEALTH AND DISEASE SCYLLO-INOSITOL AS A THERAPEUTIC FOR ALZHEIMER’S DISEASE HUMAN CLINICAL TRIALS IMMUNOTHERAPEUTIC STRATEGIES TOWARDS TREATMENT OF ALZHEIMER’S DISEASE CHAPERONE-LIKE ACTIVITY OF SITE-DIRECTED ANTIBODIES IN MODULATION OF PROTEIN CONFORMATION IN VITRO MODULATION OF BETA-AMYLOID CONFORMATION- RELATED NEUROTOXICITY BY SITE-DIRECTED ANTIBODIES CLEARANCE OF ALZHEIMER-LIKE BETA-AMYLOID PLAQUES BY MOBILISING THE IMMUNE RESPONSE ACTIVE IMMUNISATION PASSIVE IMMUNISATION INTRAVENOUS IMMUNOGLOBULIN TREATMENT PUTATIVE MECHANISMS OF AMYLOID PLAQUE REMOVAL VIA IMMUNOTHERAPY A NOVEL TARGET FOR IMMUNOTHERAPY – B-SECRETASE CLEAVAGE SITE ON APP AB PEPTIDE PRODUCTION FROM THE AMYLOID PRECURSOR PROTEIN (APP) ANTIBODIES AGAINST B-SECRETASE CLEAVAGE SITE OF APP CONCLUSIONS TAU PROTEIN AS TARGET CHAPTER ALZHEIMER NEURO?BRILLARY DEGENERATION: PIVOTAL ROLE AND THERAPEUTIC TARGETS PIVOTAL ROLE RELATIONSHIP BETWEEN B-AMYLOIDOSIS AND NEURO?BRIL- LARY DEGENERATION MOLECULAR MECHANISM OF NEURO?BRILLARY DEGENERA- TION REGULATION OF TAU PHOSPHORYLATION THERAPEUTIC TARGETS MULTIPLE ROLES OF GLYCOGEN SYNTHASE KINASE-3 IN ALZHEIMER’S DISEASE GSK-3 FUNCTION AND REGULATION GSK-3 STATUS IN ALZHEIMER’S DISEASE GSK-3 AND AB GSK-3 AND TAU GSK-3 AND PRESENILIN GSK-3: NEURONAL PLASTICITY AND MEMORY GSK-3: DIABETES AND ALZHEIMER’S DISEASE TAU PROTEIN KINASES INHIBITORS: FROM THE BENCH TO THE CLINICAL TRIALS RELEVANT TAU PROTEIN KINASES GSK-3 INHIBITORS REACH CLINICAL TRIALS LESSONS LEARNT FROM CLINICAL USE OF LITHIUM TDZDS, A WORK CASE ON CLINICAL DEVELOPMENT CDK5 IN TAU PHOSPHORYLATION CDK5 INHIBITORS CASEIN KINASE CK1 INHIBITORS INHIBITORS OF OTHER TAU PROTEIN KINASES CHAPTER 10 ACTIVATING PP2A AS A THERAPEUTIC INTERVENTION STRATEGY IN ALZHEIMER’S DISEASE MAINTENANCE OF SIGNAL-TRANSDUCTION NETWORKS PROTEIN PHOSPHATASES: THE FORGOTTEN HALF OF SIGNAL TRANSDUCTION TAU, PHOSPHORYLATION AND ALZHEIMER’S DISEASE PATHOLOGICAL TAU HYPERPHOSPHORYLATION: THE KEY ROLE OF PP2A ACTIVATING PP2A WITH CHEMICAL AGENTS AN ALTERNATIVE STRATEGY TO LIMIT TOXIC PHOSPHOTAU FOLATE AND XYLULOSE-5-PHOSPHATE CERAMIDE-PALMITATE MEMANTINE B2 ADRENERGIC RECEPTOR AGONISTS CHAPTER 11 RATIONALE FOR TAU-AGGREGATION INHIBITOR THERAPY IN ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES THE TAU-AGGREGATION PATHOLOGY OF ALZHEIMER’S DISEASE THE MOLECULAR MECHANICS OF TAU AGGREGATION IN ALZHEIMER’S DISEASE THE BASIS OF TAU-AGGREGATION INHIBITOR THERAPY METHYLTHIONINIUM CHLORIDE AS A TAU-AGGREGATION INHIBITOR CLINICAL APPLICATION OF TAU-AGGREGATION INHIBITOR THERAPIES GLUCOSE METABOLISM AS TARGET CHAPTER 12 INSULIN RESISTANCE AND NEURODEGENERATION: TYPE-2 VERSUS TYPE-3 DIABETES MELLITUS OVERVIEW ALZHEIMER’S DISEASE INSULIN AND INSULIN-LIKE GROWTH-FACTOR SIG- NALLING HUMAN STUDIES SUPPORT THE CONCEPT THAT AD IS TYPE-3 DIABETES EXPERIMENTAL ANIMAL MODEL RESULTS THE CONCEPT OF BRAIN-INSULIN RESISTANCE DIABETES MELLITUS IN AD PATHOGENESIS CERAMIDES MAY CAUSE BRAIN-INSULIN RESIS- TANCE AND DEGENERATION IN OBESITY AND T2DM THE LIVER–BRAIN AXIS OF NEURODEGENERATION TYPE-3 DIABETES VERSUS TYPE-2 DIABETES AND NEURO- DEGENERATION TYPE-3 DIABETES MAY BE TREATABLE, PREVENTABLE, OR CURABLE WITH ANTIDIABETES DRUGS CHAPTER 13 INSULIN-LIKE GROWTH FACTOR I AS A DISEASE-MODIFYING THERAPY IN ALZHEIMER’S DEMENTIA IGF-I AND DEVELOPMENT OF AD PATHOLOGY PATHOLOGICAL TRAITS IN AD AND IGF-I FUNCTION IGF-I AND COGNITIVE DETERIORATION IGF-I AND AMYLOID PHYSIOLOGY IGF-I AND TAUOPATHY IGF-I AND THE PATHOLOGICAL CASCADE IN AD IGF-I AND INSULIN SIGNALLING IN AD IGF-I AND NEUROIN?AMMATION PATHOLOGICAL DISTURBANCES ARISING FROM BRAIN METABOLIC IMPAIRMENT MECHANISMS LEADING TO REDUCED SERUM IGF-I INPUT TO THE BRAIN SUMMARY AND PERSPECTIVES