Inducible microRNA‐34a overexpression impairs cognition and promotes Alzheimer's pathology

Abstract Background Alzheimer’s disease (AD), a chronic neurodegenerative condition resulting from pathological brain aging, is the most common cause of geriatric dementia and is likely polygenic in origin. The discovery of microRNAs (miR), small, endogenous, non‐coding, and highly conserved RNAs that regulate post‐transcriptional expression of potentially hundreds of genes, has revealed new drivers and therapeutic targets of AD pathogenesis. Research from our group and others indicates that miR‐34a may be a promising candidate. Method We aimed to interrogate the dementia‐associated cognitive and neurobiological consequences of miR‐34a stimulation in vivo . We generated a global doxycycline (Doxy)‐inducible miR‐34a expression mouse model (miR34a +/‐ 2X (TetR‐TetO‐miR34a). Three‐month‐old male and female miR‐34a +/‐ mice were treated for ∼90 days with either normal drinking water or Doxy (2mg/ml) to induce miR‐34a expression (N= 7‐8 mice/group) and evaluated for cognitive and neurobiological factors disrupted in other transgenic AD mice. To ascertain brain‐ and cell type‐specific vulnerabilities of miR‐34a overexpression, we also generated a mutant mouse line in which miR‐34a overexpression is restricted to excitatory neurons using a CaMKIIα driver. Result Doxy‐treated miR‐34a +/‐ mice showed T/Y‐maze memory deficits, coinciding with upregulated miR‐34a expression in all brain regions assayed. They also showed evidence of known AD neuropathologies, including reduced NMDA2B glutamatergic receptor expression, altered amyloid precursor processing (alpha‐secretase), and increased phosphorylated tau. Experiments to determine consequences of brain‐specific miR‐34a overexpression are ongoing. Conclusion In conclusion, miR‐34a appears to contribute to an AD‐like phenotype. Future work will utilize this Tet‐inducible system to explore age‐related susceptibility to, and capacity for recovery from, the cognitive and neuropathological consequences of miR‐34a overexpression.