Small RNA, big impact Profiling the therapeutic potential of microRNA-132 in Alzheimer's disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with no effective disease-modifying treatments. The multifactorial nature of AD underscores the need for therapeutics that address multiple pathological pathways. MicroRNAs (miRNAs) are promising candidates due to their multitargeting nature and ability to regulate diverse molecular networks. Among them, miR-132 is notably downregulated in AD and has been linked to amyloid deposition, Tau pathology, synaptic plasticity, and memory decline. However, understanding its full regulatory effects, particularly in microglia and neurogenesis, is crucial for assessing its therapeutic potential.
This thesis investigates the role of miR-132 in two key aspects of AD pathophysiology: neuroinflammation and adult hippocampal neurogenesis (AHN). First, a multi-omics approach was used to profile the miR-132 targetome in the mouse hippocampus, revealing its role in microglial activation and disease-associated microglial states. In human induced pluripotent stem cell (iPSC)-derived microglia, miR-132 modulation influenced gene expression and inflammatory responses, supporting its relevance in AD.
Second, miR-132’s effect on AHN was examined by identifying its potential targets at the interphase between AD and AHN. NACC2 was identified as a key miR-132-regulated gene affecting neural stem cell differentiation, with potential relevance to AD.
Overall, this thesis provides novel insights into miR-132’s regulatory roles in immune and neurogenic functions, highlighting its promise as a multi-target therapeutic strategy for AD. However, its pleiotropic effects necessitate careful evaluation to balance therapeutic benefits and potential risks.