Reprogramming to alleviate Alzheimer’s disease through ameliorating microglial inflammation and neuronal damage

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, characterized by glial cell dysfunction and progressive neuron loss, leading to varying degrees of neuropathology and cognition impairment. Aging and epigenetic alterations accompany the progression of AD and disrupt cellular functions; therefore, whether reprogramming could restore epigenetic information while maintaining cellular identity remains unclear.MethodThe polycistronic expression cassette contained multiple transcription factors of the Oct4, Sox2, and Klf4 genes (OSK) that were cloned into a coexpression vector (Ad‐OSK). The effects of OSK on cognitive function and neuropathology were explored in 4‐month‐old and 6‐month‐old APP/PS1 transgenic AD model mice via stereotaxic injection into the bilateral hippocampus.ResultAd‐OSK maintained microglial and neuronal cellular identities while attenuating microglia‐induced neuroinflammation and neuronal apoptosis. Ectopic expression of OSK in mouse brain tissue alleviates and restores cognitive function, youthful neuronal pathogenesis, Aβ plaque deposition, microglial activation, and myelin damage in early stage and later stage AD mice, respectively. The DNA demethylation process is required for the beneficial effects of OSK induced reprogramming in brain health.ConclusionThese results suggest that brain tissues preserve youthful epigenetic information, which is primarily stored by DNA demethylation during OSK reprogramming and can be accessed to improve brain health in AD mice. Our findings provide the foundation for the future use of OSK adenovirus or mRNA medicine to treat AD.