title: Differential release of β-amyloid from dendrite- versus axon-targeted APP.
abstract: The β-amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease. APP is processed in neurons, but little is known about the relative contributions of presynaptic or postsynaptic compartments to the release of Aβ peptides. To address this issue, we transduced primary neurons from Sprague-Dawley rats or APP(-/-) mice (B6.129S7-App(tm1Dbo)/J) with lentiviral constructs expressing APP chimeras harboring targeting motifs from low-density lipoprotein receptor or neuron-glia cell-adhesion molecule to polarize expression to either dendritic or axonal membranes, respectively. Using imaging and quantitative biochemical approaches, we now report that APP selectively targeted to either axons or dendrites leads to the secretion of full-length Aβ peptides with significantly elevated release from dendritic compartments. These findings reveal that the enzymatic machinery required for production of Aβ peptides are operative both in presynaptic and postsynaptic compartments of primary neurons, leading to the suggestion that Aβ-mediated impairments in glutamatergic neurotransmission is the result of Aβ release from both local and distal neuronal compartments.
authors.affiliation: Medical Scientist Training Program, Committee on Neurobiology, and.
authors.forename: Scott R
authors.initials: SR
authors.lastname: DeBoer
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Georgia
authors.initials: G
authors.lastname: Dolios
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, and ssisodia@bsd.uchicago.edu.
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor
keywords: APP; Aβ; amyloid precursor protein; axonal targeting; dendritic targeting; β-amyloid