A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimer's Disease.

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. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-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 microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.