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:Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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A Trisomy 21-Associated Hotspot CSF2RB Mutation in Human Microglia Confers Resilience to Alzheimer’s Disease (scRNA-Seq)

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