Microglial motility and morphology in Alzheimer's Disease, and after Aβ42- immunotherapy

Microglia are the resident immune cells of the brain. Their main functions in the adult brain are to provide protection against pathogens and to remove cellular debris via phagocytosis. Microglial function is highly dependent on cell motility. Evidence from Alzheimer’s disease (AD) animal models supports microglial motility impairment in AD, possibly linked to Aβ accumulation. In AD patients immunised against Aβ42, Aβ plaque removal is partly due to phagocytic microglia, supporting an association between microglial function and Aβ clearance. The aim of the present study is to evaluate the expression of microglial motility-related proteins, as well as microglial morphological features, in the inferior parietal lobule of 32 controls, 44 AD cases and 16 immunised AD (iAD) cases, patients who had been immunised against the Aβ42 peptide. Immunohistochemistry (IHC) was performed for the proteins Iba1, CFL1, CORO1A and P2RY12, and protein load was assessed with an automated image analysis method. The neuroinflammatory environment was evaluated with Meso Scale Discovery protein immunoassays. Iba1 IHC was also used for microglial cell counting and morphological analysis. Fluorescent Iba1 IHC, confocal microscopy and semi-automated 3Dreconstruction were used for detailed assessment of microglial morphological features. Among the most relevant results, the levels of the motility-related proteins studied showed no difference in AD cases compared to controls. In the iAD group compared to AD, the levels of Iba1 were increased in grey and white matter, and the level of P2RY12 in the grey matter only.There was no difference in the total number of microglia in AD compared to controls, but there was an increase in iAD compared to AD. The ramified population was reduced in AD compared to controls, while in iAD both the ramified and amoeboid populations were increased. The microglial cell body volume was increased in AD compared to controls, whereas the total process length was increased in iAD compared to AD. Our results highlight some potentially relevant effects of the disease, and of Aβimmunotherapy on microglial motility, and help further our understanding of the functional spectrum of microglia in health and disease

Dataset for: Load of motility-related microglial proteins, inflammation-related proteins, and microglial morphological features in controls, Alzheimer's Disease (AD) cases, and AD cases after Aβ42-immunotherapy

Data underpinning the findings of the PhD thesis &quot;Microglial motility and morphology in AD and after amyloid-beta-42-immunotherapy&quot; </span

Molecular mechanisms of microglial motility: changes in ageing and Alzheimer’s disease

Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their morphology to adapt to their environment. The microglial motility and morphological versatility are the result of a complex molecular machinery, mainly composed of mechanisms of organization of the actin cytoskeleton, coupled with a “sensory” system of membrane receptors that allow the cells to perceive changes in their microenvironment and modulate their responses. Evidence points to microglia as accountable for some of the changes observed in the brain during ageing, and microglia have a role in the development of neurodegenerative diseases, such as Alzheimer’s disease. The present review describes in detail the main mechanisms driving microglial motility in physiological conditions, namely, the cytoskeletal actin dynamics, with emphasis in proteins highly expressed in microglia, and the role of chemotactic membrane proteins, such as the fractalkine and purinergic receptors. The review further delves into the changes occurring to the involved proteins and pathways specifically during ageing and in Alzheimer’s disease, analyzing how these changes might participate in the development of this disease

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

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 cases from our unique group of patients immunised against Aβ42 (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-Aβ, Aβ42 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 Aβ 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 Aβ appears during the ageing process, the homeostatic Iba1 and P2RY12 –positive microglia respond to Aβ, but this response is absent in AD. Aβ immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in control