Amyloid precursor protein cytoplasmic domain antagonizes reelin neurite outgrowth inhibition of hippocampal neurons.
The function of the amyloid precursor protein (APP), a key molecule in Alzheimer's disease (AD) remains unknown. Among the proteins that interact with the APP cytoplasmic domain in vitro and in heterologous systems is Disabled-1, a signaling molecule of the reelin pathway. The physiological consequence of this interaction is unknown. Here we used an in vitro model of hippocampal neurons grown on a reelin substrate that inhibits neurite outgrowth. Our results show that an excess of APP cytoplasmic domain internalized by a cell permeable peptide, is able to antagonize the neurite outgrowth inhibition of reelin. The APP cytoplasmic domain binds Disabled-1 and retains it in the cytoplasm, preventing it from reaching the plasma membrane and sequesters tyrosine phosphorylated Disabled-1, both of which disrupt reelin signaling. In the context of AD, increased formation of APP cytoplasmic domain in the cytosol released after cleavage of the A beta peptide, could then inhibit reelin signaling pathway in the hippocampus and thus influence synaptic plasticity.
Hoareau
C
C
INSERM U796, Centre Paul Broca, 2 ter rue d'Alésia, 75014 Paris, France.
Borrell
V
V
Soriano
E
E
Krebs
M O
MO
Prochiantz
A
A
Allinquant
B
B
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors* / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000737:chemistry / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases