title: Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer's disease.
abstract: Besides formation of neurofibrillary tangles and neuron loss, the Alzheimer's disease brain is characterized by neuritic plaques consisting of beta-amyloid peptide deposits and impaired neurotransmission. The proteins Munc18a, Munc18-interacting protein 1 and Munc18-interacting protein 2 mediate exocytosis and decrease beta-amyloid peptide formation. Cyclin-dependent kinase 5 and its activator p35 disrupt Munc18a-syntaxin 1 binding, thereby promoting synaptic vesicle fusion during exocytosis. We investigated protein levels of the signaling pathway: p35, cyclin-dependent kinase 5, Munc18a, syntaxin 1A and 1B, Munc18-interacting protein 1 and Munc18-interacting protein 2 in Alzheimer's disease cortex and found that this pathway was up-regulated in the Alzheimer's disease parietal and occipital cortex. In the cortex of transgenic Tg2576 mice over-expressing human beta-amyloid precursor protein with the Swedish mutation known to lead to familial Alzheimer's disease, which have substantial levels of beta-amyloid peptide but lack neurofibrillary tangles and neuron loss, no alterations of protein levels were detected. These data suggest that the pathway is enhanced in dying or surviving neurons and might serve a protective role by compensating for decreased neurotransmission and decreasing beta-amyloid peptide levels early during the progression of Alzheimer's disease.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Guy's, King's and St Thomas' Schools of Biomedical Sciences, King's College London, St. Thomas Street, London SE1 1UL, UK. e.jacobs@erasmusmc.nl
authors.forename: E H
authors.initials: EH
authors.lastname: Jacobs
authors.forename: R J
authors.initials: RJ
authors.lastname: Williams
authors.forename: P T
authors.initials: PT
authors.lastname: Francis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D002102:Cadaver; D002423:Cause of Death; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D051938:Munc18 Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000473:pathology; D015854:Up-Regulation
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C513072:Apba1 protein, mouse; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D051360:Cyclin-Dependent Kinase 5