The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology Aβ1‐42 induces pore‐like.

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The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology Aβ1‐42 induces pore‐like step ionic current increases across lipid bilayer membranes and grows with inverted sign after voltage inversion to amplifier saturation current. In the presence of anle138b, the current remains at low amplitude and does not increase beyond 30 pA. Expanded trace of anle138b‐treated membrane presented in (A). Discreet conductance levels are highlighted suggesting multiple opening and closing events for three individual pores. Hippocampal neurons (DIV 10) were treated with anle138b (1 μM) or vehicle before Aβ1‐40 oligomers or monomers were added (10 μM, n = 4/group). After 48 h, membrane integrity was measured as fluorescence intensity using a CyQUANT assay (Thermo Fisher). In the vehicle group, membrane integrity was significantly impaired when treated with Aβ oligomers comparing with control neurons or Aβ monomer‐treated neurons, anle138b‐treated neurons did not exhibit a difference between addition of Aβ monomers or Aβ oligomers (t‐test, **P = 0.007). Same experimental setting as in (C) but cell viability was measured using the MTT assay (t‐test, *P = 0.002 vs. control). No difference in cell viability was observed for Aβ monomer or oligomer treatment in the absence or presence of anle138b. Schematic of potential mechanisms of activity inhibition for anle138b. In the absence of anle138b, Aβ monomers and/or oligomers insert in the membrane and form conducting pores. Treatment with anle138b renders these conductive channels inactive most probably due to reduced life time of the open state. Data information: Error bars indicate SEM. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. EMBO Mol Med, Volume: 10, Issue: 1, Pages: 32-47, First published: 05 December 2017, DOI: (10.15252/emmm.201707825)