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Microglial pathology in Down syndrome

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Abstract

Subjects with Down syndrome (DS) inevitably develop histopathological features pathognomonic of Alzheimer’s disease (AD), and DS can therefore be considered a human model of AD. Similar to AD, microglial activation has been reported in DS and the idea that detrimental neuroinflammation plays a key role in the pathogenesis of neurodegeneration is firmly embedded. However, recent work from this laboratory has offered evidence for an alternative view regarding the role of microglial cells in AD pathogenesis by showing presence of dystrophic (senescent) rather than activated microglia in both the AD and DS brain. In this report, we build on previously published observations in human brain and offer a detailed analysis of microglial senescent pathology in the temporal cortices of 6 DS cases in their 40s, a critical age bracket where virtually all DS subjects acquire neurofibrillary degeneration characteristic of AD. Our findings using both Iba1 and anti-ferritin immunostaining of microglial cells show that coincident with the appearance of tau pathology in DS subjects there is consistent presence of dystrophic microglial cells and conspicuous absence of activated microglia using both markers. The extent of microglial pathology varied among the individual DS cases, but they all revealed decreased numbers of normal microglia ranging from 19 to 85% of the controls. Nearly all of the ferritin-positive microglia, which constitute a subset of the total Iba1-reactive microglial population, exhibited dystrophic morphology. In its most severe form dystrophy was evident as total fragmentation of the cells’ cytoplasm (cytorrhexis), which likely reflects terminal degeneration of microglia. Severely dystrophic, ferritin-positive cells were often found to be colocalized with tau-positive senile plaques. Our findings help to consolidate the idea that microglial degeneration and neurofibrillary degeneration are closely linked events in a human model of AD. They suggest that microglial degeneration follows a gradually progressive course that increases in its severity in parallel with the progression of AD neurodegenerative changes.

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Acknowledgments

Supported by NIH grant AG023665.

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Authors and Affiliations

  1. Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, PO Box 100244, Gainesville, FL, 32610-0244, USA

    Qing-Shan Xue & Wolfgang J. Streit

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  1. Qing-Shan Xue
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  2. Wolfgang J. Streit
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Correspondence to Wolfgang J. Streit.

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Xue, QS., Streit, W.J. Microglial pathology in Down syndrome. Acta Neuropathol 122, 455–466 (2011). https://doi.org/10.1007/s00401-011-0864-5

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