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Microglial motility in Alzheimer's disease and after A?42 immunotherapy: a human post-mortem study.

ABSTRACT: 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? 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?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?, A?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? 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? appears during the ageing process, the homeostatic Iba1 and P2RY12 -positive microglia respond to A?, but this response is absent in AD. A?-immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in controls.

SUBMITTER: Franco-Bocanegra DK

PROVIDER: S-EPMC6842157 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Microglial motility in Alzheimer's disease and after Aβ42 immunotherapy: a human post-mortem study.

Franco-Bocanegra Diana K DK George Bethany B Lau Laurie C LC Holmes Clive C Nicoll James A R JAR Boche Delphine D

Acta neuropathologica communications 20191108 1

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 Aβ immunotherapy using post-mortem brain tissue of 32 controls, 44 AD cases, and 16 AD case ...[more]

PMID: 31703599

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Project description:BackgroundDepression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls.MethodsWe assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18-50-year-olds with depression, 30 older individuals (ages 51-90) with depression, 28 with early AD (Braak tangle stages III-IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aβ, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood-brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry.ResultsThere was no evidence of chronic cerebral hypoperfusion or increased Aβ/tau in either depression group. There was also no indication of pericyte damage, increased blood-brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups.ConclusionsContrary to some previous findings, we have not found evidence of impaired vascular function or increased Aβ in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency.

Dataset Information

Microglial motility in Alzheimer's disease and after A?42 immunotherapy: a human post-mortem study.

Publications

Microglial motility in Alzheimer's disease and after Aβ42 immunotherapy: a human post-mortem study.

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