Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice

Abstract

Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously demonstrated that a treatment of inducing Plagl2, a zinc finger transcription factor gene, and antagonizing Dyrk1a, a gene associated with Down syndrome, referred to as iPaD, can functionally rejuvenate aged neural stem cells (NSCs), thereby enhancing neurogenesis and improving cognition in aged mice. Here, we found that NSC-specific iPaD treatment effectively activated neurogenesis, reduced amyloid-{beta} deposition, and improved cognitive function in Alzheimers disease model mice. Transcriptomic analysis revealed widespread significant changes in gene expression in the hippocampus following iPaD treatment. The upregulated genes included those associated with the activation of astrocytes and microglia involved in amyloid-{beta} clearance, while the downregulated genes included several that are upregulated in Alzheimers disease patients, but whose roles in disease progression remain unclear. Among the latter genes, knockdown of Prkag2, a gene encoding protein kinase AMP-activated non-catalytic subunit gamma 2, in the hippocampus most effectively enhanced neurogenesis and reduced amyloid-{beta} accumulation. Notably, both iPaD treatment and Prkag2 knockdown activated AMP-activated protein kinase signaling, thereby upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimers disease.