Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice

Geroscience. 2022 Feb;44(1):173-194. doi: 10.1007/s11357-021-00408-z. Epub 2021 Aug 19.


C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer's disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.

Keywords: Age; Cognition; Entorhinal cortex; Full-length tau; LTP; Neurodegeneration; Tauopathy; Truncated tau.

Publication types

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

MeSH terms

  • Alzheimer Disease* / genetics
  • Animals
  • Cognition
  • Cognitive Dysfunction* / pathology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity