Abstract
Amyloid precursor protein (APP), a transmembrane glycoprotein, is well known for its involvement in the pathogenesis of Alzheimer disease of the aging brain, but its normal function is unclear. APP is a prominent component of the adult as well as the developing brain. It is enriched in axonal growth cones (GCs) and has been implicated in cell adhesion and motility. We tested the hypothesis that APP is an extracellular matrix adhesion molecule in experiments that isolated the function of APP from that of well-established adhesion molecules. To this end we plated wild-type, APP-, or β1-integrin (Itgb1)- misexpressing mouse hippocampal neurons on matrices of either laminin, recombinant L1, or synthetic peptides binding specifically to Itgb1 s or APP. We measured GC adhesion, initial axonal outgrowth, and substrate preference on alternating matrix stripes and made the following observations: Substrates of APP-binding peptide alone sustain neurite outgrowth; APP dosage controls GC adhesion to laminin and APP-binding peptide as well as axonal outgrowth in Itgb1− independent manner; and APP directs GCs in contact guidance assays. It follows that APP is an independently operating cell adhesion molecule that affects the GC's phenotype on APP-binding matrices including laminin, and that it is likely to affect axon pathfinding in vivo.
Highlights
Amyloid precursor protein (APP) and its two isoforms, APP-like proteins 1 and 2 (APLP1, 2), are transmembrane glycoproteins of the plasma membrane encoded by separate genes
APP is Present in growth cones (GCs) Adhesions on Laminin Western blot analyses of GCs (GCPs) isolated by density gradient fractionation from newborn brain confirmed in mouse that APP was highly enriched in GCs
In order to assess whether APP was present in GC adhesions to laminin, we plated live GC ‘‘particles’’ (GCPs) isolated from fetal rat brain on laminin and extracted them with the mild detergent Brij98
Summary
Amyloid precursor protein (APP) and its two isoforms, APP-like proteins 1 and 2 (APLP1, 2), are transmembrane glycoproteins of the plasma membrane encoded by separate genes. They are subject to cleavage by three different proteases, which may release the Ab peptide implicated in the pathogenesis of Alzheimer disease of the adult or aging brain [1,2,3]. APP is abundant in growth cones (GCs) and has been implicated in cell migration and neurite outgrowth [11,14,15,16,17,18,19].
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