Influence of Host Age on Intracranial AAV9 TauP301LInduced Tauopathy

Amber M. Tetlow, Brianna M. Jackman, Mohammed M. Alhadidy, Varshini Perumal, David G. Morgan, Marcia N. Gordon

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Advanced age is the greatest risk factor for the development of Alzheimer's disease (AD). This implies that some aspect of the aged milieu is possibly accelerating the development of AD related pathologies. Objective: We hypothesized that intracranially injected with AAV9 tauP301L may cause a greater degree of pathology in old versus young mice. Methods: Animals were injected with viral vectors overexpressing the mutant tauP301L or control protein (green fluorescent protein, GFP) into the brains of mature, middle-aged, and old C57BL/6Nia mice. The tauopathy phenotype was monitored four months after injection using behavioral, histological, and neurochemical measures. Results: Phosphorylated-tau immunostaining (AT8) or Gallyas staining of aggregated tau increased with age, but other measures of tau accumulation were not significantly affected. Overall, AAV-tau injected mice had impaired radial arm water maze performance, increased microglial activation, and showed evidence of hippocampal atrophy. Aging impaired open field and rotarod performance in both AAV-tau and control mice. The efficiency of viral transduction and gene expression were the same at all animal ages. Conclusion: We conclude that tauP301L over expression results in a tauopathy phenotype with memory impairment and accumulation of aggregated tau. However, the effects of aging on this phenotype are modest and not detected by some markers of tau accumulation, similar to prior work on this topic. Thus, although age does influence the development of tauopathy, it is likely that other factors, such as ability to compensate for tau pathology, are more responsible for the increased risk of AD with advanced age.

Original languageEnglish
Pages (from-to)365-378
Number of pages14
JournalJournal of Alzheimer's Disease
Volume93
Issue number1
DOIs
StatePublished - 2 May 2023
Externally publishedYes

Keywords

  • Adeno-associated virus
  • aging
  • animal disease models
  • tauopathy

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