Neuronal cell cycle re-entry enhances neuropathological features in AppNLFKnock-In Mice

Tomás Barrett, Katherine A. Stangis, Takashi Saito, Takaomi Saido, Kevin H.J. Park

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Aberrant cell cycle re-entry is a well-documented process occurring early in Alzheimer's disease (AD). This is an early feature of the disease and may contribute to disease pathogenesis. Objective: To assess the effect of forced neuronal cell cycle re-entry in mice expressing humanized Aβ, we crossed our neuronal cell cycle re-entry mouse model with AppNLF knock-in (KI) mice. Methods: Our neuronal cell cycle re-entry (NCCR) mouse model is bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. The NCCR mice were crossed with AppNLF KI mice to generate NCCR-AppNLF animals. Using this tet-off system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. The animals were examined at the following time points: 9, 12, and 18 months of age. Various neuropathological features in our mice were evaluated by image analysis and stereology on brain sections stained using either immunofluorescence or immunohistochemistry. Results: We show that neuronal cell cycle re-entry in humanized Aβ plaque producing AppNLF KI mice results in the development of additional AD-related pathologies, namely, pathological tau, neuroinflammation, brain leukocyte infiltration, DNA damage response, and neurodegeneration. Conclusion: Our findings show that neuronal cell cycle re-entry enhances AD-related neuropathological features in AppNLF mice and highlight our unique AD mouse model for studying the pathogenic role of aberrant cell cycle re-entry in AD.

Original languageEnglish
Pages (from-to)1683-1702
Number of pages20
JournalJournal of Alzheimer's Disease
Volume82
Issue number4
DOIs
StatePublished - 2021

Keywords

  • Alzheimer's disease
  • DNA damage response
  • amyloid-β
  • brain leukocyte infiltration
  • cell cycle
  • neuroinflammation
  • tau

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