Targeted Musashi1 knockdown leads to reduce tau pathology and improves cognitive function in aged P301L mouse model

Abstract Background The buildup of toxic tau species in the brain is thought to lead to the development of Alzheimer’s disease. While our current understanding of the mechanisms underlying this aggregation is limited, growing evidence has pointed to RNA‐binding proteins (RBPs) playing a role. The dysregulation of RBPs is associated with various neurodegenerative diseases. For example, during amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), dysregulated TDP‐43 accumulates in the brain. Similarly, our recent studies showed that the RBP, Musashi‐1 (MSI1), may co‐aggregate with toxic tau oligomers in Alzheimer’s disease. Clarifying the connection between these two proteins may provide novel insights into the mechanisms behind toxic tau buildup in Alzheimer’s, allowing for new therapeutic targets in treatment development. Method In this study, we investigated the role of MSI1 on the aggregation and deposition of tau in aged (18‐months old) P301L mouse models, which express the P301L mutant form of tau. MSI1 expression was knocked down (KD) by performing intracerebroventricular injections of MSI1 antisense oligonucleotides into the hippocampus. The effects of MSI1 KD on tau accumulation and pathology were studied in the hippocampus, cortex, and cerebellum. Result Western blot and immunofluorescence (IF) analysis revealed a significant reduction in MSI1 and tau proteins levels and aggregation in the P301L mouse brain, mainly in the hippocampus. Furthermore, brain Co‐IF microscopy and Dot Blot analysis of the PBS‐ and Sarkosyl‐soluble fractions showed that there was a significant reduction of MSI1 and tau oligomeric species in the hippocampus, cortex, and cerebellum in MSI1 KD mice. In addition, phosphorylated tau forms (pSer422, pSer202/Thr205, pThr212/Ser214 and pThr231/Ser235) were significantly decreased in the cortex, cerebellum, and most prominently, in the hippocampus. Increase in synaptic marker Synaptophysin suggesting an increase of synaptogenesis. Behavioral tests, Novel Object Recognition (NOR) and Y‐Maze spontaneous alternations tests, MSI1‐KD mice showed significant improvements. Conclusion These results suggest that MSI1 plays a major role in tau toxicity, revealing it as a possible target for treating Alzheimer’s disease.