Neuronal protein trafficking associated with Alzheimer disease: from APP and BACE1 to glutamate receptors.
Aberrant and/or cumulative amyloid-beta (Abeta) production, resulting from proteolytic processing of the amyloid precursor protein (APP) by beta and gamma-secretases, have been postulated to be a main etiological basis of Alzheimer disease (AD). A number of proteins influence the subcellular trafficking itinerary of APP and the beta-site APP-cleaving enzyme (BACE1) between the cell surface, endosomes and the trans-Golgi network (TGN). Available evidence suggests that co-residence of APP and BACE1 in the endosomal compartments promotes amyloidogenesis. Retrograde transport of APP out of the endosome to the TGN reduces Abeta production, while APP routed to and kept at the cell surface enhances its non-amyloidogenic, alpha-secretase-mediated processing. Changes in post-Golgi membrane trafficking in aging neurons that may influence APP processing is particularly relevant to late-onset, idiopathic AD. Dystrophic axons are key features of AD pathology, and impaired axonal transport could play crucial roles in the pathogenesis of idiopathic AD. Recent evidence has also indicated that Abeta-induced synaptic defects and memory impairment could be explained by a loss of both AMPA and NMDA receptors through endocytosis. Detail understanding of factors that influence these neuronal trafficking processes will open up novel therapeutic avenues for preventing or delaying the onset of symptomatic AD.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. bchtbl@nus.edu.sg
Bor Luen
BL
Tang
D000544:Alzheimer Disease / Q000201:enzymology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001370:Axonal Transport; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D017470:Receptors, Glutamate / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D017470:Receptors, Glutamate; D016282:Aspartic Acid Endopeptidases