A Mechanism for the Inhibition of Tau Neurotoxicity: Studies with Artificial Membranes, Isolated Mitochondria, and Intact Cells

Segev Naveh Tassa, Shani Ben Zichri, Shiran Lacham-Hartman, Ofek Oren, Zeev Slobodnik, Ekaterina Eremenko, Debra Toiber, Raz Jelinek, Niv Papo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


It is currently believed that molecular agents that specifically bind to and neutralize the toxic proteins/peptides, amyloid β (Aβ42), tau, and the tau-derived peptide PHF6, hold the key to attenuating the progression of Alzheimer's disease (AD). We thus tested our previously developed nonaggregating Aβ42 double mutant (Aβ42DM) as a multispecific binder for three AD-Associated molecules, wild-Type Aβ42, the tauK174Q mutant, and a synthetic PHF6 peptide. Aβ42DM acted as a functional inhibitor of these molecules in in vitro assays and in neuronal cell-based models of AD. The double mutant bound both cytotoxic tauK174Q and synthetic PHF6 and protected neuronal cells from the accumulation of tau in cell lysates and mitochondria. Aβ42DM also reduced toxic intracellular levels of calcium and the overall cell toxicity induced by overexpressed tau, synthetic PHF6, Aβ42, or a combination of PHF6and Aβ42. Aβ42DM inhibited PHF6-induced overall mitochondrial dysfunction: In particular, Aβ42DM inhibited PHF6-induced damage to submitochondrial particles (SMPs) and suppressed PHF6-induced elevation of the ζ-potential of inverted SMPs (proxy for the inner mitochondrial membrane, IMM). PHF6 reduced the lipid fluidity of cardiolipin/DOPC vesicles (that mimic the IMM) but not DOPC (which mimics the outer mitochondrial membrane), and this effect was inhibited by Aβ42DM. This inhibition may be explained by the conformational changes in PHF6 induced by Aβ42DM in solution and in membrane mimetics. On this basis, the paper presents a mechanistic explanation for the inhibitory activity of Aβ42DM against Aβ42-and tau-induced membrane permeability and cell toxicity and provides confirmatory evidence for its protective function in neuronal cells.

Original languageEnglish
Pages (from-to)1563-1577
Number of pages15
JournalACS Chemical Neuroscience
Issue number9
StatePublished - 5 May 2021


  • Alzheimer's disease
  • Aβ42
  • PHF6
  • Tau
  • amyloids
  • neurodegeneration

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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