Differential Release of ß-Amyloid from Dendrite- Versus Axon-Targeted APP

The beta-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 A beta 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 A beta peptides with significantly elevated release from dendritic compartments. These findings reveal that the enzymatic machinery required for production of A beta peptides are operative both in presynaptic and postsynaptic compartments of primary neurons, leading to the suggestion that A beta-mediated impairments in glutamatergic neurotransmission is the result of A beta release from both local and distal neuronal compartments.