Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1.
BACKGROUND
Beta-amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-alpha) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood.


RESULTS
Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo. Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-alpha, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-alpha is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-alpha and the deletion of APP are inhibited by blocking antibodies to Integrin beta1 (Itgbeta1). Moreover, full length APP interacts biochemically with Itgbeta1, and APPs-alpha can interfere with this binding.


CONCLUSIONS
Our findings indicate that APPs-alpha regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgbeta1.
Young-Pearse
Tracy L
TL
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. tyoung@rics.bwh.harvard.edu
Chen
Allen C
AC
Chang
Rui
R
Marquez
Cesar
C
Selkoe
Dennis J
DJ
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; C498283:Aplp2 protein, rat; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins