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Neurodegenerative disorders

Choice cuts?

Nature Reviews Neuroscience volume 8, page 9 (2007)Cite this article

In the first study, reported in Nature Medicine, Ni and colleagues sought to investigate how the pathogenesis of Alzheimer's disease is influenced by environmental factors such as stress, which is mediated by receptors including the β2-adrenoceptor (β2-AR). Using cell-based assays, they found that β2-AR-activation increased the secretion of Aβ, which was blocked by pretreatment with a γ-secretase inhibitor. Subsequent experiments using an assay of the activity of γ-secretase indicated that the β2-agonist-induced increase in Aβ secretion was due to increased γ-secretase activity.

Next, the authors probed the mechanism for enhanced γ-secretase activity. After finding that the activity enhancement was independent of cyclic AMP signalling, they discovered that endocytosis inhibitors or small interfering RNA against clathrin — a protein involved in the formation of endocytotic vesicles — abolished β2-AR-induced γ-secretase activity. So, β2-AR-induced enhancement of γ-secretase activity is dependent on clathrin-mediated endocytosis. Further experiments revealed that the β2-AR directly associates with with presenilin 1 — the catalytic subunit of g-secretase — which was trafficked to late endosomes and lysosomes where Aβ production was elevated.

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ORIGINAL RESEARCH PAPERS

  1. Ni, Y. et al. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nature Med. 19 Nov 2006 (doi: 10.1038/nm1485)

  2. Willem, M. et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science 314, 664–666 (2006)

    Article  CAS  Google Scholar 

  3. Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nature Neurosci. 9, 1520–1525 (2006)

    Article  CAS  Google Scholar 

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  1. Associate Editor, Nature Reviews Drug Discovery,

    Charlotte Harrison

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  1. Charlotte Harrison
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Harrison, C. Choice cuts?. Nat Rev Neurosci 8, 9 (2007). https://doi.org/10.1038/nrn2062

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  • DOI: https://doi.org/10.1038/nrn2062

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