miR-449a mediated repression of the cell cycle machinery prevents neuronal apoptosis

Aberrant activation of the cell cycle of terminally differentiated neurons results in their apoptosis and is known to contribute to neuronal loss in various neurodegenerative disorders like Alzheimer's Disease. However, the mechanisms that regulate cell cycle-related neuronal apoptosis are poorly understood. We identified several miRNA that are dysregulated in neurons from a transgenic APP/PS1 mouse model for AD (TgAD). Several of these miRNA are known to and/or are predicted to target cell cycle-related genes. Detailed investigation on miR-449a revealed the following: a, it promotes neuronal differentiation by suppressing the neuronal cell cycle; b, its expression in cortical neurons was impaired in response to amyloid peptide Aβ₄₂; c, loss of its expression resulted in aberrant activation of the cell cycle leading to apoptosis. miR-449a may prevent cell cycle-related neuronal apoptosis by targeting cyclin D1 and protein phosphatase CDC25A, which are important for G1-S transition. Importantly, the lentiviral-mediated delivery of miR-449a in TgAD mouse brain significantly reverted the defects in learning and memory, which are associated with AD.