Project description:While challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Recent studies indicate that somatic mutations in hematopoietic cells may lead to both the instigation and resilience to neurodegeneration. Down syndrome (DS), or trisomy 21, is the most significant genetic risk factor for AD. Interestingly, some DS individuals show resilience to AD neuropathology and do not exhibit dementia signs. Notably, DS individuals face a heightened risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Microglia dysfunction is a central mechanism in AD etiology. Here we hypothesize that somatic mutations associated with DS myeloid leukemia may impart resilience to microglia against AD. Using CRISPR-Cas9 gene editing, we introduce a DS-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses type-1 interferon signaling in both DS and control human microglia, independent of trisomy 21 genetic background. This mutation also reduces neuroinflammation and enhances phagocytic and autophagy functions, ameliorating senescent and dystrophic changes in human microglia. Furthermore, the CSF2RB A455D mutation promotes the development of a microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize, outcompete, and gradually replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest the potential use of hPSC-derived CSF2RB A455D microglia to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need of depleting endogenous senescent microglia prior to cell transplantation.

Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.

Dataset Information

Neurogenin-2 Reprograms Human Microglial Lineage Cells into Neurons In Vitro and in Chimeric Brains

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets