Far from being innocent bystanders to pathology, amyloid plaques actively stir up trouble by perturbing the brain tissue surrounding them, according to researchers led by Mark Fiers and Bart De Strooper at KU Leuven, Belgium. In a preprint on bioRxiv, the authors had previously reported that plaques in a mouse model of amyloidosis kick off a coordinated cellular response that ramps up inflammation and represses myelination (Aug 2019 news). The study is now published in the July 17 online Cell, with the addition of data from human postmortem brains that replicate many of the changes seen in mice. The paper features stunning images from spatial transcriptomics, and made the cover of the journal’s August issue.
- In mice, microglia and astrocytes near plaques switch on inflammatory and lysosomal genes.
- Oligodendrocytes dampen myelination genes.
- In Alzheimer’s brain, it’s a similar story.
Joint first authors Wei-Ting Chen and Ashley Lu analyzed the transcriptome in tissue slices from the brains of APPNL-G-F knock-in mice. This approach preserved spatial information, allowing them to detect expression changes that occurred around plaques. The authors followed this up with in situ sequencing of the altered genes to identify the cell types that expressed these genes.
They found that as plaques grew, nearby microglia and astrocytes revved up a suite of 57 plaque-induced genes (PIGs). Most were involved in the complement cascade and other aspects of the immune response, or the endosomal-lysosomal system. Meanwhile, oligodendrocytes responded differently. Early in plaque development, these cells boosted myelination genes (OLIGs), perhaps to compensate for white-matter damage. As amyloidosis advanced, these genes went silent, and oligodendrocytes instead turned on some inflammatory genes.
To see if these results were relevant to human disease, the authors analyzed postmortem superior frontal gyrus tissue from three Alzheimer’s brains at Braak stages V to VI and three age-matched controls. The authors analyzed these samples with in situ sequencing, but not spatial transcriptomics. Sequencing of more than 200 genes revealed changes similar to those in mice, with microglia and astrocytes turning up inflammation, and oligodendrocytes dialing down myelination.
Of the 57 mouse PIGs, 45 had human orthologs, and 18 of these were highly expressed near plaques. Others of the 45 were elevated in AD brains, but not pinpointed to plaques. Mouse OLIGs had 42 human orthologs. Of those, 22 were down near plaques, but five were higher. A few genes that were expressed by oligodendrocytes in mice turned up in other cell types in human AD brain. For example, the immune gene CYBA and the lysosomal gene LAPTM5 were enriched in human microglia, the redox sensor NMRAL1 in neurons, and the protein aggregation regulators CRYAB and GSN in astrocytes. The authors noted that, unlike the mouse model, AD brains contain neurofibrillary tangles and dying cells, and that may alter some cellular responses.
The human data closely match previous studies of how gene expression changes in postmortem AD brain tissue, which also reported PIGs up and OLIGs down (May 2013 webinar; Jun 2018 news). These previous studies did not localize the differences to specific cell types or plaque halos, however.
Similar gene-expression changes have been found in spinal cord samples from amyotrophic lateral sclerosis patients and in a mouse model of frontotemporal dementia, suggesting that some of these alterations may represent a general response to neurodegeneration (Maniatis et al., 2019; Mar 2019 news).
The findings in this paper are freely available in an online database that allows users to perform their own analyses of the expression data.—Madolyn Bowman Rogers
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Research Models Citations
- Maniatis S, Äijö T, Vickovic S, Braine C, Kang K, Mollbrink A, Fagegaltier D, Andrusivová Ž, Saarenpää S, Saiz-Castro G, Cuevas M, Watters A, Lundeberg J, Bonneau R, Phatnani H. Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science. 2019 Apr 5;364(6435):89-93. PubMed.
- Chen WT, Lu A, Craessaerts K, Pavie B, Sala Frigerio C, Corthout N, Qian X, Laláková J, Kühnemund M, Voytyuk I, Wolfs L, Mancuso R, Salta E, Balusu S, Snellinx A, Munck S, Jurek A, Fernandez Navarro J, Saido TC, Huitinga I, Lundeberg J, Fiers M, De Strooper B. Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease. Cell. 2020 Jul 17; PubMed.