Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-019-0828-x
Keywords
Human microglia; Cell motility; Alzheimer's disease; A beta-immunotherapy; Neuroinflammation
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Funding
- CONACyT scholarship [270152 / 438262]
- University of Southampton scholarship [VCFoM/BocheD/TBC/170]
- Alzheimer's Research UK [ART/PG2006/4, ART-EXT2010-1, ARUK-EG2015A-4]
- MRC [G0501033] Funding Source: UKRI
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Microglial function is highly dependent on cell motility, with baseline motility required for homeostatic surveillance activity and directed motility to migrate towards a source of injury. Experimental evidence suggests impaired microglial motility in Alzheimer's disease (AD) and therefore we have investigated whether the expression of proteins associated with motility is altered in AD and affected by the A beta immunotherapy using post-mortem brain tissue of 32 controls, 44 AD cases, and 16 AD cases from our unique group of patients immunised against A beta 42 (iAD). Sections of brain were immunolabelled and quantified for (i) the motility-related microglial proteins Iba1, cofilin 1 (CFL1), coronin-1a (CORO1A) and P2RY12, and (ii) pan-A beta, A beta 42 and phosphorylated tau (ptau). The neuroinflammatory environment was characterised using Meso Scale Discovery multiplex assays. The expression of all four motility-related proteins was unmodified in AD compared with controls, whereas Iba1 and P2RY12, the homeostatic markers, were increased in the iAD group compared with AD. Iba1 and P2RY12 showed significant positive correlations with A beta in controls but not in the AD or iAD groups. Pro- and anti-inflammatory proteins were increased in AD, whereas immunotherapy appears to result in a slightly less pro-inflammatory environment. Our findings suggest that as A beta appears during the ageing process, the homeostatic Iba1 and P2RY12 -positive microglia respond to A beta, but this response is absent in AD. A beta-immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in controls.
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