Aberrant cell cycle activation in terminally differentiated neurons leads to apoptosis and contributes to neuronal loss in neurodegenerative diseases like Alzheimer's Disease (AD). However, the mechanisms underlying cell cycle-related neuronal apoptosis remain poorly understood.
In a transgenic APP/PS1 mouse model of AD (TgAD), researchers identified several dysregulated miRNAs, many of which target cell cycle-related genes. Notably, miR-449a plays a key role in neuronal function by: (a) promoting neuronal differentiation through cell cycle suppression, (b) showing impaired expression in cortical neurons exposed to amyloid-β (Aβ42), and (c) preventing aberrant cell cycle activation and apoptosis. miR-449a likely exerts its protective effect by targeting cyclin D1 and CDC25A, key regulators of the G1-S transition.
Importantly, lentiviral delivery of miR-449a in TgAD mouse brains significantly restored learning and memory deficits associated with AD, highlighting its therapeutic potential.
Reference:
Chauhan, M., Singh, K., Chongtham, C., A G, A., & Sharma, P. (2024). miR-449a mediated repression of the cell cycle machinery prevents neuronal apoptosis. The Journal of biological chemistry, 300(9), 107698. https://doi.org/10.1016/j.jbc.2024.107698