Nuclear signalling by membrane protein intracellular domains: the AICD enigma.
Alzheimer's disease (AD) is a neurodegenerative illness and the leading cause of dementia in the elderly. The accumulation of amyloid-β peptide (Aβ) is a well-known pathological hallmark associated with the disease. However, Aβ is only one of several metabolites produced by β- and γ-secretase actions on the transmembrane protein, the amyloid precursor protein (APP). A proteolytic fragment termed the APP intracellular domain (AICD) is also produced. By analogy with the Notch signalling pathway, AICD has been proposed as a transcriptional regulator although its mechanism of action and the complement of genes regulated remain controversial. This review will focus on the contributions that studies of APP processing have brought to the understanding of a novel nuclear signalling pathway that may contribute to the pathology of AD and may provide new therapeutic opportunities.
Institute of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Caroline
C
Beckett
Institute of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK; I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg, Russia.
Natalia N
NN
Nalivaeva
Institute of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Nikolai D
ND
Belyaev
Institute of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address: a.j.turner@leeds.ac.uk.
Anthony J
AJ
Turner
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin