Neuronal Cell Cycle Re-Entry Enhances Neuropathological Features in App(NLF) Knock-In Mice

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 App(NLF) 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 App(NLF) KI mice to generate NCCR-App(NLF) 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 App(NLF) 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 App(NLF) mice and highlight our unique AD mouse model for studying the pathogenic role of aberrant cell cycle re-entry in AD.