An Alzheimer's disease hypothesis based on transcriptional dysregulation.
Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by progressive loss of memory and other cognitive skills. Neurons in the limbic and association cortices become progressively dysfunctional affecting almost all cognitive functions and memory. The PSI-regulated epsilon-secretase cleavage of type I transmembrane receptors controls production of transcriptionally active intracellular fragments (ICFs) suggesting that this cleavage is a key factor in surface-to-nucleus signal transduction and gene expression. Signal-induced gene expression mediates neuronal responses to environmental changes and is a key event in neuronal survival and synaptic function. Familial Alzheimer's Disease (FAD) mutations may interfere with nuclear signaling and transcription by interfering with the PS1/epsilon-secretase cleavage and production of transcriptionally active ICFs. This raises the possibility that, similar to polyglutamine induced neurodegeneration like Huntington's chorea, transcriptional abnormalities are involved in the development of FAD.
Robakis
Nikolaos K
NK
Department of Psychiatry, Fishberg Reserch Center for Neurobiology, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, NY 10029, USA. nikos.robakis@mssm.edu
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D014158:Transcription, Genetic
D001053:Apolipoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D000685:Serum Amyloid A Protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human