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Menassa, D. A.

Publications and source records attributed to Menassa, D. A..

2 recordsLinked to original sources

Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

Microglia, the brains resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 postmortem tissues enabling quantitative, sex-matched, detailed analysis of microglial across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

neuroscience

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology

The sustained proliferation of microglia is a key hallmark of Alzheimers disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased {beta}gal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of A{beta} and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early A{beta} pathology in AD.

neuroscience