Single nucleus RNA sequencing of glia in Alzheimer's disease brains post mortem
Amy M. Smith1,2, Sandra Silva Guedes1, Prashant Srivastava1, Steve Gentleman1, David Owen1 and Paul M. Matthews1,2 Division of Brain Sciences1 and UK Dementia Research Institute2, Imperial College London, UK
Microglia play many roles in Alzheimer's disease pathogenesis and increasing evidence suggests their involvement in early disease processes as well as increasing risk of disease [1,2]. Vascular changes, involving disruption of the blood-brain barrier, are common and early features of dementia-associated pathology [3,4]. However, our knowledge of the relationship between vascular pathology and microglial disease phenotypes is limited. This project investigates the diversity of microglia and macrophage phenotypes in relation to endothelial cells in the human brain in the context of aging and dementia.
We have applied a combination of immunohistochemistry and RNASeq to characterize microglia and endothelial cells from human post-mortem tissue from the Brains for Dementia Research brain bank. Histological characterisation of microglial and vascular changes is being performed in tissue from a range of Alzheimer's disease stages and neurological controls across three brain areas: entorhinal cortex, middle temporal gyrus and primary somatosensory cortex. Immunohistochemistry allows well-characterised areas of tissue to be selected for RNA sequencing.
We are using single nuclear RNA sequencing  to characterise the transcriptomic changes in microglia and the endothelium, studying post mortem brain tissue. Differential gene expression and network analysis  is being performed to characterise changes with disease progression and generate hypotheses regarding molecular disease mechanisms. We will present initial results, highlighting quality control measures and demonstrating the feasibility of such analyses and their potential relevance for re-purposing existing molecules as experimental therapeutics. References:
Keren-Shaul et al. 2017, Cell.
Li and Barres 2017, Nature Reviews Immunology.
Nelson et al. 2016, Biochimica et BioPhysica Acta.
Goodall et al. 2017, Neuropathol Appl Neurobiol.
Krishnaswami et al. 2016, Nature Protocols.
Johnson et al. 2015, Nature Neuroscience.
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