In Alzheimer's disease (AD), toxic amyloid-β42 (Aβ42) binds to and aberrantly signals through the α7-nicotinic acetylcholine receptor (α7nAchR). Using tissue from both mouse models of AD and patients with AD, this study showed that Aβ42 signalling is dependent upon the recruitment of the scaffolding protein filamin A to the α7nAchR. An orally available small molecule that bound to filamin A (PTI-125) reduced abnormal signalling of α7nAChRs, decreased levels of tau phosphorylation and Aβ aggregates, and prevented Aβ-induced inflammatory cytokine release. PTI-125 greatly reduced the affinity of Aβ42 for α7nAChRs and could dissociate existing Aβ42–α7nAChR complexes.
ORIGINAL RESEARCH PAPER
Wang, H.-Y. et al. Reducing amyloid related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J. Neurosci. 32, 9773–9784 (2012)
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Harrison, C. Targeting filamin A reduces Alzheimer's signalling. Nat Rev Drug Discov 11, 674 (2012). https://doi.org/10.1038/nrd3832
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DOI: https://doi.org/10.1038/nrd3832