Abolishing Tau cleavage by caspases at Aspartate 421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

Transl Psychiatry. 2017 Aug 8;7(8):e1198. doi: 10.1038/tp.2017.165.

Abstract

TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate421, to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called TauDN-that expresses a Tau mutant that cannot be cleaved by caspases. TauDN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aspartic Acid / metabolism*
  • Behavior, Animal / physiology
  • Brain / metabolism*
  • Brain / pathology
  • Caspases / metabolism*
  • Memory / physiology*
  • Memory Disorders / metabolism*
  • Memory Disorders / pathology
  • Mice
  • Mice, Transgenic
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neuronal Plasticity / physiology*
  • Phosphorylation
  • tau Proteins / metabolism*

Substances

  • tau Proteins
  • Aspartic Acid
  • Caspases