Genetic and molecular aspects of Alzheimer's disease shed light on new mechanisms of transcriptional regulation.
Rapid advances made in biological research aimed at understanding the molecular basis of the pathogenesis of Alzheimer's disease have led to the characterization of a novel catalytic activity termed gamma-secretase. First described for its beta-amyloid-producing function, gamma-secretase is now actively studied for its role in a novel signal transduction paradigm, which implicates cell-surface receptor proteolysis and direct surface-to-nucleus signal transduction. gamma-Secretase targets numerous type I protein receptors involved in diverse functions ranging from normal development to neurodegeneration. In this Review we discuss how the study of the genetic and molecular aspects of Alzheimer's disease has revealed a dual role of gamma-secretase in transcriptional regulation and in the pathogenesis of familial Alzheimer's disease.
Marambaud
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Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA. philippe.marambaud@mssm.edu
Robakis
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D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D016282:Aspartic Acid Endopeptidases; D015820:Cadherins / Q000096:biosynthesis; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; C502403:FAT1 protein, human; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human