title: Decreased rabphilin 3A immunoreactivity in Alzheimer's disease is associated with Aβ burden.
abstract: Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer's disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca(2+)-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand Rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ25-35 peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Clinical Research, Singapore General Hospital, Singapore.
authors.forename: Michelle G K
authors.initials: MG
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chingli
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jasinda H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
authors.affiliation: Department of Pharmacology, School of Medicine, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ramírez
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Memory, Aging and Cognition Centre (MACC), National University Health System, Singapore.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Memory, Aging and Cognition Centre (MACC), National University Health System, Singapore.
authors.forename: Peter T-H
authors.initials: PT
authors.lastname: Wong
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Memory, Aging and Cognition Centre (MACC), National University Health System, Singapore. Electronic address: mitchell.lai@dementia-research.org.
authors.forename: Mitchell K P
authors.initials: MK
authors.lastname: Lai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D000097624:Rabphilin-3A
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D033921:Vesicular Transport Proteins; D000097624:Rabphilin-3A; C074636:amyloid beta-protein (25-35)
keywords: Alzheimer’s disease; Amyloid-β; Dementia; Rabphilin; SNARE complex; Synapse