Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment

Neurobiol Aging. 2011 Jan;32(1):1-14. doi: 10.1016/j.neurobiolaging.2010.09.008. Epub 2010 Oct 18.

Abstract

The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that the generation of β-amyloid (Aβ) triggers Tau neurofibrillary pathology. Recently a "17 kD" calpain-induced Tau fragment, comprising residues 45-230 (molecular weight [MW], 18.7 kD), was proposed to mediate Aβ-induced toxicity. Here, we demonstrate that the "17 kD" fragment is actually much smaller, containing residues 125-230 (molecular weight, 10.7 kD). Inducing Tau phosphorylation by okadaic acid or mimicking phosphorylation by Glu mutations at the epitopes of Alzheimer-diagnostic antibodies AT100/AT8/PHF1 could not prevent the generation of this fragment. The fragment can be induced not only by Aβ oligomers, but also by other cell stressors, e.g., thapsigargin (a Ca(2+)-ATPase inhibitor) or glutamate (an excitatory neurotransmitter). However, overexpression of neither Tau(45-230) nor Tau(125-230) fragment is toxic to Chinese hamster ovary (CHO) cells, neuroblastoma cells (N2a) or primary hippocampal neurons. Finally, the calpain-induced fragment can be observed both in Alzheimer's disease brains and in control normal human brains. We conclude that the 17 kD Tau fragment is not a mediator of Aβ-induced toxicity, leaving open the possibility that upstream calpain activation might cause both Tau fragmentation and toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Calmodulin-Binding Proteins / pharmacology
  • Calpain / pharmacology*
  • Cell Count
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Cricetinae
  • Cricetulus
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Glutamic Acid / pharmacology
  • Green Fluorescent Proteins / genetics
  • Humans
  • In Situ Nick-End Labeling / methods
  • Molecular Weight
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptide Fragments / toxicity
  • Peptides / metabolism
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Rats
  • Thapsigargin / pharmacology
  • Transfection / methods
  • tau Proteins / drug effects*
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • ADD3 protein, human
  • Amyloid beta-Peptides
  • Calmodulin-Binding Proteins
  • Enzyme Inhibitors
  • Peptide Fragments
  • Peptides
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Green Fluorescent Proteins
  • Glutamic Acid
  • Thapsigargin
  • Calpain