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Low concentrations of aggregated β-amyloid induce neurite formation via the neurotrophin receptor p75

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Abstract

Aggregated β-amyloid (Aβ) 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 Aβ in higher concentrations (10–100 μM) is known to cause apoptosis via p75, our experiments focused on the effects of low concentrations of Aβ (25 nM) which may occur in early stages of Alzheimer disease. Application of Aβ 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. Aβ 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, Aβ led to quick formation, branching and elongation of processes. But while NGF distinctly promoted neurite branching and elongation, Aβ 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 Aβ and p75.

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Acknowledgements

We thank Dr. R. Heumann for his support of our work and Dr. C. Herrmann for providing the RBD-GST construct. K.S. was supported by Friedrich-Ebert-Stiftung.

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  1. Ruhr-Universität Bochum, Fakultät Chemie, Biochemie II, 44790, Bochum, Germany

    K. Susen & A. Blöchl

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Susen, K., Blöchl, A. Low concentrations of aggregated β-amyloid induce neurite formation via the neurotrophin receptor p75. J Mol Med 83, 720–735 (2005). https://doi.org/10.1007/s00109-005-0671-3

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