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

Anjanet Loon, Frank Zamudio, Awa Sanneh, Breanna Brown, Shayna Smeltzer, Milene L. Brownlow, Zainuddin Quadri, Melinda Peters, Edwin Weeber, Kevin Nash, Daniel C. Lee, Marcia N. Gordon, Dave Morgan, Maj Linda B. Selenica

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)173-194
Number of pages22
JournalGeroScience
Volume44
Issue number1
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
This work was supported by Seed Grant funds from the College of Pharmacy, Byrd Alzheimer’s Institute at the University of South Florida, and NIH grant R01 AG 051500 to DGM.

Publisher Copyright:
© 2021, American Aging Association.

Keywords

  • Age
  • Cognition
  • Entorhinal cortex
  • Full-length tau
  • LTP
  • Neurodegeneration
  • Tauopathy
  • Truncated tau

ASJC Scopus subject areas

  • Aging
  • Veterinary (miscellaneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice'. Together they form a unique fingerprint.

Cite this