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Vol. 54, Issue 3, 469-526, September 2002

Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease

Yoo-Hun Suh and Frederic Checler

Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea (Y.-H.S.); and Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France (F.C.)

I. Introduction
II. Amyloid Precursor Protein
    A. Structure of Amyloid Precursor Protein
    B. Trafficking and Proteolytic Processing of Amyloid Precursor Protein
        1. alpha -Secretase.
        2. beta -Secretase.
        3. gamma -Secretase.
        4. Caspases.
        5. Amyloid-Degrading Enzymes.
            a. Insulin-Degrading Enzyme.
            b. Neprilysin.
            c. Plasmin.
            d. Endothelin-Converting Enzyme.
            e. Other Candidate Proteases.
    C. Amyloid Cascade Hypothesis: Two Major Amyloid Precursor Protein Metabolites Involved in Alzheimer's Disease Pathogenesis
        1. Amyloid beta -Peptide Hypothesis.
            a. Neurotoxic Mechanisms of Amyloid beta -Peptide: Free Radical Accumulation, Altered Calcium Homeostasis, and Inflammatory Response.
                i. Free-Radical Accumulation.
                ii. Altered Calcium Homeostasis.
                iii. Inflammatory Response.
                iv. Activation of Signaling Pathways.
        2. C-Terminal Fragment Hypothesis.
            a. Neurotoxic Mechanisms of C-Terminal Fragment of beta -Amyloid Precursor Protein.
                i. In Vivo Generation of Amyloidogenic Carboxyl-Terminal Fragments of beta -Amyloid Precursor Protein.
                ii. Toxicity of Carboxyl-Terminal Fragments.
            b. The Involvement of Carboxyl-Terminal Fragments of Amyloid Precursor Protein in Gene Transactivation.
    D. Amyloid and Tau
    E. Transgenic Models of Amyloidogenesis
        1. APPswe Transgenic Mice (Tg2576).
        2. Amyloid Precursor Protein V717F Transgenic Mice (PDAPP Mice).
        3. APP-751swe/V717I Transgenic Mice.
        4. TgAPP23.
        5. C100/C104 Transgenic Mice.
III. Presenilin
    A. Preliminary Remarks
    B. Cell Biology of Presenilins
    C. Presenilins and Their Molecular Partners
    D. Physiological and Pathological Roles of Presenilins.
        1. Presenilins and the gamma -Secretase Cleavage of beta -Amyloid Precursor Protein.
        2. Presenilins and Notch Signaling.
        3. Presenilins and Programmed Cell Death.
        4. Presenilins and the Unfolded-Protein Response.
        5. Other Putative Functions of Presenilins.
            a. Presenilin As a Receptor/Channel.
            b. Presenilin in Cell Adhesion.
            c. Other Putative Functions.
    E. Concluding Remarks on Presenilin Physiology
IV. alpha -Synuclein
    A. Molecular and Cell Biology of alpha -Synuclein
    B. Putative Functions of alpha -Synuclein in Cell Death
    C. alpha -Synucleinopathies
    D. alpha -Synuclein: A Bridge between Parkinson's and Alzheimer's Pathologies
V. Therapeutic Targets for Alzheimer's Disease
    A. Agents Affecting Secretary Amyloid Precursor Protein-alpha
    B. Acetylcholinesterase Inhibitors
        1. Tacrine Hydrochloride (Cognex).
        2. Donepezil Hydrochloride (Aricept).
        3. Galantamine (Reminyl).
        4. Rivastigmine Tartrate (Exelon).
    C. Agents Inhibiting Aggregation of Amyloid Precursor Protein Metabolites
        1. Metal Chelators.
        2. beta -Sheet Breakers.
    D. Antioxidants
    E. Anti-Inflammatory Agents
    F. Estrogens
    G. Vaccines
    H. beta -Secretase Inhibitors
    I. gamma -Secretase Inhibitors
        1. Peptidic Inhibitors.
        2. Nonpeptidic Inhibitors.
            a. JLK Inhibitors.
Acknowledgments
References

Alzheimer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing beta -amyloid (Abeta ) derived from amyloid precursor protein (APP) and tau -rich neurofibrillary tangles. To date, the cause and progression of both familial and sporadic AD have not been fully elucidated. The autosomal-dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding APP, presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). APP is processed by several different proteases such as secretases and/or caspases to yield Abeta and carboxyl-terminal fragments, which have been implicated in the pathogenesis of Alzheimer's disease. Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of Abeta and alpha -synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. Recent studies have strongly suggested the possible pathogenic interactions between Abeta , presenilins, and/or alpha -synuclein. Therefore, treatments that block the accumulation of Abeta and alpha -synuclein might benefit a broad spectrum of neurodegenerative disorders. This review covers the trafficking and processing of APP, amyloid cascade hypothesis in AD pathogenesis, physiological and pathological roles of presenilins, molecular characteristics of alpha -synuclein, their interactions, and therapeutic strategies for AD.

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Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics

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