Dataset Information

Transcriptional signature in microglia associated with Aβ plaque phagocytosis

ABSTRACT: The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here we isolated amyloid plaque-containing (using labelling with methoxy–XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4- microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Nathan Croft

LAB HEAD: Nathan Croft

PROVIDER: PXD024731 | Pride | 2021-04-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20171102_Nathan_Wt-Ad-AdMe_AD1.wiff	Wiff
	20171102_Nathan_Wt-Ad-AdMe_AD1.wiff.scan	Wiff
	20171102_Nathan_Wt-Ad-AdMe_AD2.wiff	Wiff
	20171102_Nathan_Wt-Ad-AdMe_AD2.wiff.scan	Wiff
	20171102_Nathan_Wt-Ad-AdMe_AD3.wiff	Wiff

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Publications

Transcriptional signature in microglia associated with Aβ plaque phagocytosis.

Grubman Alexandra A Choo Xin Yi XY Chew Gabriel G Ouyang John F JF Sun Guizhi G Croft Nathan P NP Rossello Fernando J FJ Simmons Rebecca R Buckberry Sam S Landin Dulce Vargas DV Pflueger Jahnvi J Vandekolk Teresa H TH Abay Zehra Z Zhou Yichen Y Liu Xiaodong X Chen Joseph J Larcombe Michael M Haynes John M JM McLean Catriona C Williams Sarah S Chai Siew Yeen SY Wilson Trevor T Lister Ryan R Pouton Colin W CW Purcell Anthony W AW Rackham Owen J L OJL Petretto Enrico E Polo Jose M JM

Nature communications 20210521 1

The role of microglia cells in Alzheimer's disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associ ...[more]

PMID: 34021136

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.