Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation

J Alzheimers Dis. 2016 Oct 18;54(4):1521-1538. doi: 10.3233/JAD-150960.


Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

Keywords: Alzheimer’s disease; caspases; neurodegenerative diseases; protein aggregation; tau proteins; tauopathies.

MeSH terms

  • Animals
  • Caspase Inhibitors / pharmacology*
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Copper-Transporting ATPases / chemistry
  • Copper-Transporting ATPases / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Protein Conformation / drug effects
  • Staurosporine / pharmacology
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • Caspase Inhibitors
  • Enzyme Inhibitors
  • MAPT protein, human
  • tau Proteins
  • Caspases
  • ATP7A protein, human
  • Copper-Transporting ATPases
  • Staurosporine