APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP).
Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory. Full-length APP binds the low-density lipoprotein receptor-related protein (LRP), which stimulates APP endocytosis. LRP also contributes to neurite growth. Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP-LRP interactions. To elucidate APP contributions to neurite growth for full-length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPPα and/or RAP and measured neurite outgrowth at 1 day in vitro. Our data reveal that WT neurons had less axonal outgrowth including less axon branching. RAP treatment potentiated the inhibitory effects of APP. KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation. Our results affirm a major inhibitory role by full-length APP on all aspects of axonal and dendritic outgrowth, and show that RAP-LRP binding stimulated axon growth independently of APP. These findings support a major role for APP as an inhibitor of neurite growth and reveal novel signaling functions for LRP that may be disrupted by Alzheimer's pathology or therapies aimed at APP processing.
Center of Excellence in Neurosciences, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX 79905, USA.
Andrew J
AJ
Billnitzer
Irina
I
Barskaya
Cailing
C
Yin
Ruth G
RG
Perez
D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D009570:Nitriles / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D002070:Butadienes; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009570:Nitriles; D014404:Tubulin; C113580:U 0126