Therapeutic effects of anti-amyloid-beta immunotherapy on myeloid cell transcriptome
Eva Mracsko, Tobias Bergauer, Martin Ebeling, Roland Schmucki, Balazs Banfai, Irene Knuesel Roche Innovation Center Basel
Microglia and other resident CNS innate immune cells play key roles in brain homeostasis and neuronal functions. These myeloid cells in the parenchyma and CNS-adjoining tissue (macrophages in perivascular space, meninges, choroid plexus) are highly specialized and plastic. They actively survey the environment and react immediately to changes in CNS homeostasis. Supported by strong genetic evidence, their activation is essential to brain recovery and repair; but deregulated responses and failure in proper damage response can result in progressive neurodegeneration. Recent single cell RNAseq studies and microglia fate-mapping provided a first detailed molecular characterization (1) and evidence for local proliferation (2) of disease-associated myeloid cells in animal models of Alzheimer's disease. By down-regulating expression of certain homeostatic genes and up-regulation of genes for lipid metabolism and phagocytosis, the disease-associated microglia (DAMs) appear to play a crucial protective role against amyloid-beta; potentially preventing progressive neuronal damage. However, whether these DAMs can be modulated or induced pharmacologically has not been investigated yet. Here, we tested the effect of anti-amyloid-beta as well as anti-PD1 blocking immunotherapies on the transcriptional signature of plaque-associated myeloid cells (including activated microglia and infiltrating macrophages/monocytes); comparing this effect with resting microglia and blood monocytes using FACS and RNA sequencing. We find that anti-amyloid-beta immunotherapy has a strong effect on plaque-associated myeloid cells, changing their expression signature towards that seen in blood monocytes, including increased phagocytosis. Anti-PD1 immunotherapy had only minor effects and mostly on blood monocytes, increasing expression of adhesion genes. Our data provide first molecular evidence for direct modulation of plaque-associated myeloid cells by therapeutic anti-amyloid-beta antibodies.
1 Keren-Shaul et al. Cell 2017 2 Tay et al. Nat Neurosci 2017
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