BOOK COVER -- HALF-TITLE -- TITLE -- COPYRIGHT -- CONTENTS -- INTRODUCTION -- PATHOLOGY OF ALZHEIMER'S DISEASE -- 1. AMYLOID MORPHOLOGY AND PATHOLOGY OF ALZHEIMER'S DISEASE -- INTRODUCTION -- MORPHOLOGY -- Senile Plaques -- Typical plaques -- Primitive plaques -- Diffuse plaques -- Diffuse plaques associated with clusters of intra-astroglial AB-positive granules -- Compact (burned-out) plaques -- Amyloid plaques in the white matter -- Subpial B Amyloid Deposits -- B Amyloid Deposits on Extracellular-NFT -- Small Stellate Deposits -- Amyloid Angiopathy -- AB Deposits in the Extra-neural Tissues -- SIGNIFICANCE OF THE B AMYLOID DEPOSITS IN THE ALZHEIMER PATHOLOGY -- AB Deposits in Disorders Other Than Alzheimer's Disease -- B Amyloid Deposits in the Mentally Normal Subjects and Pathological Diagnosis of the Alzheimer's Disease -- Plaque Density and Clearance of the Plaques -- REFERENCES -- 2. THE TAU PROTEINS IN ALZHEIMER'S DISEASE -- INTRODUCTION -- TAU AND BRAIN FUNCTION -- A family of Closely Related Phosphoproteins -- Isoform Switches and Axonal Localization -- Microtubule Binding and Beyond -- TAU IN DISEASE -- Filaments and Tangles -- Tau Modification in Disease Brain -- Staging Tau Pathology -- Functional Implications -- TAU'S ROLE IN AD PATHOLOGY -- Cell-free Models -- Cellular and Animal Models -- Tau Modification: Common End Point or Causative Role in Disease? -- ACKNOWLEDGEMENTS -- REFERENCES -- THE GENETICS OF FAMILIAL ALZHEIMER'S DISEASE -- 3. MUTATIONS IN THREE GENES ARE ASSOCIATED WITH EARLY ONSET ALZHEIMER'S DISEASE -- GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE -- MOLECULAR GENETICS OF ALZHEIMER'S DISEASE -- The Amyloid Precursor Protein -- Apolipoprotein E -- Presenilin 1 -- Presenilin 2 -- Other Genes -- Role of BAPP, ApoE and the Presenilins in the Pathogenesis of "Sporadic" AD.

Neuropathological and Clinical Phenotypes Associated with Familial Alzheimer's Disease -- ACKNOWLEDGEMENTS -- REFERENCES -- MOLECULAR AND CELLULAR BIOLOGY OF THE B-AMYLOID PRECURSOR PROTEIN AND AMYLOID B-PEPTIDE -- 4. THE BIOLOGICAL ACTIVITIES AND FUNCTION OF THE AMYLOID PRECURSOR PROTEIN OF ALZHEIMER'S DISEASE -- INTRODUCTION -- APP, ZINC AND COPPER -- APP, COPPER TRANSPORT AND NEURONAL DEGENERATION -- AMYLOID AB AND METAL-ION BINDING -- HEPARIN BINDING IN THE FUNCTION OF APP -- THE APP MOLECULE AS A REGULATOR OF HEMOSTASIS -- Structure of the KPI Domain -- APP AS A MEDIATOR OF NEUROPROTECTION -- THE FUTURE CHALLENGE -- ACKNOWLEDGEMENTS -- REFERENCES -- 5. PROTEOLYTIC PROCESSING OF THE β-AMYLOID PRECURSOR PROTEIN -- INTRODUCTION -- The Amyloid B-Precursor Protein -- Endoproteolysis of APP -- B-secretase cleavage -- The generation of AB -- B-secretase cleavage -- Y-secretase cleavage -- CONCLUSION -- REFERENCES -- 6. BIOSYNTHESIS OF APP AND AB: MULTIPLE PATHWAYS FOR THE GENERATION OF INTRACELLULAR AB -- INTRODUCTION -- MULTIPLE PATHWAYS FOR THE GENERATION OF INTRACELLULAR AB -- Endosomal/Lysosomal Pathway -- Late B-Secretory Pathway -- ER/IC Pathway -- RELATIONSHIP BETWEEN INTRACELLULAR AND SECRETED AB -- PROCESSING OF WILD-TYPE AND MUTANT APP IN NEURONAL VERSUS NON-NEURONAL CELLS -- ACTIVITY OF Y-SECRETASE -- BIOLOGICAL SIGNIFICANCE OF THE ER/IC PATHWAY -- REFERENCES -- 7. THE CELL BIOLOGY OF AMYLOID PRECURSOR PROTEIN -- Biosynthesis, Subcellular Trafficking and Secretase Processing of Amyloid Precursor Protein -- Secretory processing of amyloid precursor protein in the biosynthetic pathway -- Endocytosis and amyloid peptide generation -- Lysosomal processing of amyloid precursor protein -- Cell biology of Y-secretase processing -- Trafficking of Amyloid Precursor Protein in Epithelial MDCK Cells.

Transport and Metabolism of Amyloid Precursor Protein in Neurons -- What source of neurons should be used -- Processing of amyloid precursor protein in neurons -- Polarized trafficking of amyloid precursor protein in neurons -- REFERENCES -- 8. THE ROLE OF AMYLOID B PEPTIDE TERMINATING AT AMINO ACID 42 IN EARLY ONSET ALZHEIMER'S DISEASE -- AMYLOID B PROTEIN DEPOSITION IN ALZHEIMER'S DISEASE -- EFFECT OF MUTATIONS THAT CAUSE EARLY ONSET FAMILIAL AD -- REFERENCES -- 9. THE BIOPHYSICS OF AMYLOID B-PROTEIN FIBRILLOGENESIS -- INTRODUCTION -- The Societal Impact of Alzheimer's Disease -- The Pathobiology of Alzheimer's Disease -- Treatment Strategies -- Nucleation-Dependent Protein Polymerization -- Establishing Useful Experimental Paradigms -- STUDIES OF THE NUCLEATION AND ELONGATION OF AB FIBRILS -- A Model System for AB Fibril Formation -- Monitoring AB Fibrillogenesis Using Quasielastic Light Scattering Spectroscopy (QLS) -- The Concentration Dependence of AB Fibrillogenesis -- A Model of AB Fibrillogenesis -- Assaying Fibrillogenesis Inhibitors -- Correlation of Primary Structure with Fibrillogenesis Kinetics -- Summary -- INTERMEDIATES IN AB FIBRILLOGENESIS -- Introduction -- Development of a Model System for AB Oligomerization -- Discovery of the AB Protofibril -- Kinetics of Protofibril Formation -- Effect of Amino Acid Substitutions in AB on Protofibril Formation -- Summary -- REFLECTIONS AND DIRECTIONS -- ACKNOWLEDGMENTS -- REFERENCES -- THE PRESENILIN GENES -- 10. THE MOLECULAR BIOLOGY OF PRESENILIN 1 -- SUMMARY -- PS1/PS2 EXPRESSION -- PS1 STRUCTURE AND LOCALIZATION -- ENDOPROTEOLYSIS -- CONSEQUENCES OF PS MUTATIONS ON ENDOPROTEOLYSIS -- BIOLOGICAL FUNCTIONS OF PS1 -- PS1 KNOCKOUT MICE -- THE ROLE OF PS IN FAD AND AB METABOLISM -- REFERENCES -- 11. MOLECULAR BIOLOGY OF PRESENILIN 2 -- INTRODUCTION -- STRUCTURE OF PRESENILIN 2.

PRESENILIN 2 EXPRESSION AND LOCALIZATION -- PRESENILIN 2 PROTEIN PROCESSING -- PRESENILIN 2 AND AB FORMATION -- CONCLUSION -- REFERENCES -- 12. PRESENILIN PROTEINS AND THEIR ROLE IN DEVELOPMENT AND NOTCH SIGNALING -- EXPRESSION PATTERNS OF PRESENILINS IN VARIOUS ORGANISMS SUGGEST A ROLE IN EMBRYOGENESIS AND CELLULAR DIFFERENTIATION -- Mammalian Presenilin Genes PS-1 and PS-2 -- C. elegans Presenilin Genes sel-12, spe-4 and cps-3 -- Xenopus laevis Presenilin Genes X-ps-α and X-ps-β -- Drosophila Melanogaster DPS -- ANALYSES OF MUTANT PHENOTYPES -- The C. elegans spe-4 Presenilin Gene Functions in Protein Transport or Sorting -- The Role of Presenilins in Notch Signaling -- Genetic Determination of Presenilin Function -- Is Alzheimer's Disease Associated with a Gain-of-Misfunction Activity of Mutant Presenilins? -- CONCLUSION -- REFERENCES -- 13. THE PROCESSING OF THE AMYLOID-PRECURSOR-PROTEIN (APP) IN PRESENILIN-1 DEFICIENT NEURONS -- TARGETING OF THE PRESENILIN-1 GENE IN EMBYONIC STEM (ES) CELLS AND GENERATION OF PS1 HOMOZYGOUS MUTANT MICE -- FUNCTIONAL INACTIVATION OF THE PRESENILIN-1 GENE -- PHENOTYPE OF PRESENILIN-1 MUTANT MICE AND CULTURED NEURONS -- METABOLISM OF ENDOGENOUSLY EXPRESSED MOUSE APP IN PRESENILIN-1 DEFICIENT NEURONS -- METABOLISM OF VIRALLY EXPRESSED HUMAN APP IN PRESENILIN-1 DEFICIENT NEURONS -- PS 1 IS A FACILITATOR OF THE CLEAVAGE OF THE INTEGRAL MEMBRANE DOMAIN OF APP WITH ANALOGY TO THE SREBP-SCAP INTERACTIONS -- FUTURE PROSPECTS: IDENTIFICATION OF THE Y-SECRETASE(S) -- REFERENCES -- 14. PRESENILINS AND THEIR ROLE IN APOPTOSIS -- OVERVIEW -- INTRODUCTION -- Background and Terminology -- Methods Used in Apoptosis Research -- PRESENILIN BIOLOGY -- Presenilins: A Role for PS2 in Apoptosis -- Presenilin 1 also Enhances Apoptosis -- Presenilins as Substrates for Caspases -- Signal Transduction Pathways Controlling Apoptosis.

Biochemical Pathways Sensitive to PS1 and PS2 -- Presenilins Regulate the JNK/NFkB Cascade -- Presenilin Mutations: Loss of function exaggerates JNK/NFkB responses -- INTEGRATION WITH ALZHEIMER PATHOPHYSIOLOGY -- Integrating Apoptosis with Amyloid -- FUTURE DIRECTIONS -- Summary -- REFERENCES -- 15. THE PHOSPHORYLATION OF PRESENILIN PROTEINS -- PHOSPHORYLATION OF FULL-LENGTH PS PROTEINS -- PHOSPHORYLATION OF PROTEOLYTIC FRAGMENTS OF PS-1 -- ALTERNATIVE PROTEOLYTIC PROCESSING IMPAIRS PHOSPHORYLATION OF THE PS-1 FRAGMENTS -- PHOSPHORYLATION OF PROTEOLYTIC FRAGMENTS OF PS-2 -- REFERENCES -- ROLE OF RISK FACTORS IN ALZHEIMER'S DISEASE -- 16. APOE AND ITS ROLE IN LATE ONSET ALZHEIMER'S DISEASE -- GENETICS OF APOE AND ALZHEIMER'S DISEASE -- NORMAL EXPRESSION AND FUNCTIONS OF APOE IN THE CNS -- EXPRESSION AND FUNCTIONS OF APOE IN AD -- Levels of apoE in the CNS -- Effects of apoE on Neuronal Cells -- Interactions Between apoE and Amyloid -- A CRITICAL ROLE FOR LRP IN AD? -- REFERENCES -- TRANSGENIC MODELS FOR ALZHEIMER'S DISEASE -- 17. TRANSGENIC ANIMAL MODELS IN THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR ALZHEIMER'S DISEASE -- INTRODUCTION -- CONSIDERATIONS FOR MODEL GENERATION -- GENERATION OF TRANSGENIC MOUSE LINES OVEREXPRESSING APP -- DEVELOPMENT OF Aβ DEPOSITS IN CORTEX AND HIPPOCAMPUS OF APP 22 AND APP 23 TRANSGENIC MICE -- INFLAMMATORY PROCESSES IN BRAINS OF APP TRANSGENIC MICE -- DYSTROPHIC AND DISTORTED NEURITES INCLUDING CHOLINERGIC FIBERS IN THE VICINITY OF PLAQUES -- PLAQUE LOAD DEPENDENT NEURONAL LOSS IN THE HIPPOCAMPUS -- DISTORTED PROCESSES CONTAINING HYPERPHOSPHORYLATED TAU IN COMPACT PLAQUES -- VALIDITY OF THE MODEL AND IMPLICATIONS FOR THE MECHANISM OF AD -- OTHER TRANSGENIC ANIMAL MODELS -- USE FOR DRUG STUDIES -- REFERENCES -- 18. PRESENILINS IN TRANSGENIC MICE -- APP TRANSGENIC MODELS -- PRESENILIN TRANSGENIC MODELS.

Transgenic Crosses.