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Background: Microglia are phagocytic cells that play multiple critical roles in Alzheimer's disease susceptibility and progress. In parallel, they display remarkable diversity in their functional and molecular states in the context of disease. This suggests that a diverse portfolio of microglial subtypes modulates outcomes in AD, but the molecules that link microglia state to their function remain unknown. To address this question, we have probed whether microglia phagocytic states are regionally specified by brain neurons via a particular neuron‐derived receptor‐ligand pair – signal regulatory protein alpha (SIRPα) and CD47. Methods: To investigate the role of SIRPα, we use cell‐specific loss‐ and gain‐of‐function genetic approaches together with murine AD models. Results: Our data surprisingly show that neuron‐derived SIRPα is crucial for regulating microglial phagocytic function and phagocytic state in the context of AD. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47‐SIRPα signaling, thereby permitting microglia phagocytosis. In addition, we show that neuronal SIRPα alters microglia state by regulating microglia phagocytosis in a brain‐region specific manner. We have also identified AD pathology changes and cognitive dysfunction that are limited by neuronal SIRPα‐driven microglial phagocytosis. Conclusion: We show that neuronal SIRPα is a permissive cue for microglial phagocytosis in AD and is required to restrict AD progression and cognitive decline. Identification of a neuron‐derived mechanism that dictates microglia state plasticity is unexpected and changes the way we understand how neurons program microglia outcomes in the context of disease. Results from this study also help lay the groundwork for new therapeutic options to regionally modify brain microglia state and function. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3-dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA(LR)), we found that CUG repeats in the 3' untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1. [ABSTRACT FROM AUTHOR]