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

Abstract

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.

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Identifiers

ORCID for Delphine Boche: orcid.org/0000-0002-5884-130X

ORCID for James Nicoll: orcid.org/0000-0002-9444-7246

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