Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75.
Aggregated beta-amyloid (Abeta) binds to the neurotrophin receptor p75 and induces signaling. We examined this signaling process in different cell lines which express p75 either naturally (Schwannoma RN22 cells) or which are stably transfected with wild-type p75 (MDCKwt and PCNA cells) or with a truncated form of p75 comprising only extracellular and transmembrane domains (MDCKtm cells). While Abeta in higher concentrations (10-100 microM) is known to cause apoptosis via p75, our experiments focused on the effects of low concentrations of Abeta (25 nM) which may occur in early stages of Alzheimer disease. Application of Abeta caused tyrosine phosphorylation of wild-type p75 and induced the Ras-ERK pathway as has been reported for nerve growth factor (NGF). Since Ras activation and ERK phosphorylation (via MEK) could not be observed in MDCKtm cells and since they were clearly reduced in cells transfected with a p75 antisense construct, these effects should have been mediated by p75. Abeta also induced Ras and ERK activation in cerebellar neurons of 2-day-old rats which express p75 at that developmental stage but not TrkA; other Trk receptors were inhibited by K252a. In these neurons, Abeta led to quick formation, branching and elongation of processes. But while NGF distinctly promoted neurite branching and elongation, Abeta was less effective in neurite elongation and counts of small processes and of growth cones remained clearly elevated after 24-h stimulation; these peculiarities might be linked to aberrant neuronal connections reported for an animal model of Alzheimer disease. Essentially, the observed effects were mediated by interaction of Abeta and p75.
Ruhr-Universität Bochum, Fakultät Chemie, Biochemie II, 44790 Bochum, Germany.
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D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D026121:Indole Alkaloids; D016501:Neurites / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
D016229:Amyloid beta-Peptides; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D020800:Receptor, Nerve Growth Factor; C049985:staurosporine aglycone; D011494:Protein Kinases