Systematic assessment of microRNA‐132 therapeutic targeting in Alzheimer’s disease

Abstract Background Mapping the mechanistic heterogeneity and multifactorial nature of AD is a key challenge for therapeutic development and the main reason why network biology and multi‐modal therapies begin to attract attention also in AD research. miRNA‐targeted therapeutics are particularly suited for such purposes, as they regulate multiple components of several molecular cascades converging on disease‐relevant patho‐phenotypes. MicroRNA‐132 (miR‐132), a potent neuroimmune regulator, has been identified as the most robustly and significantly downregulated microRNA in the brain of Alzheimer’s Disease (AD) patients and its deficiency has been functionally linked to amyloid deposition, TAU hyperphosphorylation, neuronal cell death and memory decline, in human and rodents. Of note, miR‐132 can explain a higher percentage of the observed variance in histopathological AD phenotypes than APOE e4, a major risk factor for AD, while more recent evidence functionally links miR‐132 to neuroinflammation. These observations suggest that miR‐132‐dependent network‐based gene regulation in human AD brain converges onto biological pathways that can drive disease endophenotypes. Direct miR‐132 infusion in the AD mouse brain can counteract several aspects of pathology and memory deficits, providing a proof‐of‐concept of its therapeutic relevance. Despite the great benefit of the multi‐targeting nature of microRNAs for treating multifactorial diseases such as AD, this approach also entails the risk of on‐ and off‐ target toxicity, highlighting the importance of systematic genome‐wide target validation. While specific miR‐132 targets with direct implications in amyloid and TAU pathologies have been previously identified, the complex multicellular miR‐132 targetome involved in the disease progression of AD remains elusive, and is a crucial requirement for therapeutic targeting. Method In order to systematically profile the mechanisms underpinning the regulatory effects of miR‐132 in AD, we employed an RNA‐sequencing approach to assess transcriptomic responses to changes in the levels of miR‐132 in AD‐relevant study systems, such as human iPSC‐derived neurons and microglia‐like cells. Result We identify novel miR‐132 targets with putative neuroimmune functions possibly involved in AD pathophysiology. Conclusion Our results shed light on the involvement of miR‐132 in AD and further add to the systematic profiling of miR‐132 targetome, a prerequisite for successful translation of miR‐132 supplementation in AD.