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Review
. 2019 Jun 25;8(6):639.
doi: 10.3390/cells8060639.

Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer's Disease

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Free PMC article
Review

Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer's Disease

Diana K Franco-Bocanegra et al. Cells. .
Free PMC article

Abstract

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.

Keywords: Alzheimer’s disease; Microglia; ageing; morphology; motility.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the different morphologies adopted by microglia in the human brain independently of age or disease. Immunolabelling for the microglial protein Iba1 shows diverse morphologies including varying number of processes and cell body shape. (A) Ramified microglia with small round cell body and several long branching processes. (B) Reactive microglia with increased cell body size and reduced length of processes. (C) Amoeboid microglia with enlarged cell body and no processes. Images A–C taken from a control aged brain. (D) Microglia clustering around Aβ plaques (*) is a feature observed only in the presence of Alzheimer-type pathology. Haematoxylin counterstaining. Scale bar = 50 μm.
Figure 2
Figure 2
(A) Depiction of the different actin structures present in microglia: The cell cortex (covering all the inner surface of the cell), filopodai and lamellipodia (at the leading edge), and the uropod (at the rear of the cell). (B) Mechanism of formation of the actin network includes globular actin nucleates in the form of oligomers which further polymerize into left-handed two-chained helical filaments. Filaments additionally recruit globular actin to form branches, which extend from the mother filament at a characteristic 70° angle enabling filaments to easily connect with each other forming an intricate and highly plastic network.
Figure 3
Figure 3
Representation of the mechanisms of action of microglial actin-interacting proteins. (A) The process of branching is regulated by the Arp2/3 complex, (B) which is recruited by CORO1A to an existing actin filament. Arp2/3 engages with G-actin to form a filament branch. (C) Iba1 promotes the formation of parallel actin bundles, scaffold-like structures that give shape to lamellipodia and filopodia. (D) CFL1 depolymerizes filaments to make G-actin available to form new actin structures.
Figure 4
Figure 4
Examples of microglia identified using different motility-related microglial proteins. Haematoxylin counterstaining. A—CORO1A; B—Iba1; C—CFL1; D—P2Y12. Scale bar = 50 μm.
Figure 5
Figure 5
Mechanism of activation of purinergic receptors. (A) Extracellular ATP is hydrolyzed to ADP by the action of ectonucleotide pyrophophatase/phosphodiesterases (ENPPs) or ectonucleoside triphosphate dyphosphohydrolases (ENTDPases). (B) ADP is subsequently hydrolyzed to AMP, also by ENPPs and ENTDPases. AMP is converted to adenosine by ecto-5′-nucleotidases (Ecto-5′-NTs) or alkaline phosphatases. (C) P2X cation-permeable ionotropic receptors are activated by nucleosides triphosphate. (D) G protein-coupled P2Y receptors regulate voltage-gated Ca2+ and K+ channels. (E) Adenosine-mediated P1 receptor activation results in blockade of Ca2+ channels.

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