Table 1.
Summary of the most relevant proteins involved in microglial motility: Physiological function and changes in ageing and Alzheimer’s disease highlighting the gaps in our current knowledge.
| Protein | Physiological Role | Changes in Ageing | Changes in AD and Animal Models of AD |
|---|---|---|---|
| Cytoskeletal Proteins | |||
| Actin | Main constituent of cytoskeletal microfilaments. |
Animals: unknown. Humans: Increased F-actin level; decreased stimulus-induced actin polymerization. |
Animals: Presence of CFL1-actin rods. Humans: unknown |
| Arp2/3 complex | Controls branching of actin filaments. |
Animals: unknown. Humans: Decreased expression of subunits ARPC1A and ARPC1B. |
unknown |
| CORO1A | Recruits Arp2/3 to the ends of actin filaments to initiate branching. |
Animals: Decreased expression. Humans: Decreased expression. |
unknown |
| CAPN1 | Cleaves and degrades cytoskeletal proteins, such as TLN1, ACTN1, FLNC and spectrin. |
Animals: Increased expression in aged monkeys and mice. Humans: unknown. |
unknown |
| TLN1 | Mediates integrin-cytoskeleton bonds, important for cell adhesion. |
Animals: unknown. Humans: Decreased expression. |
unknown |
| Iba1 | Involved in actin bundling and membrane ruffling. |
Animals: Increased in aged gerbils, dogs and mice. Humans: Positively correlated to MMSE score. |
Animals: Increased in APPPS1 mouse model. Humans: Positively correlated to MMSE score. |
| NM II | Essential for the contractile properties of the cytoskeleton. | unknown | unknown |
| CFL1 | Depolymerizes and severs actin filaments. |
Animals: Increased load of pCFL1, presence of CFL1-actin rods. Humans: unknown. |
Animals: Increased load of pCFL1, presence of CFL1-actin rods. Humans: Increased load of pCFL1, presence of CFL1-actin rods. |
| SSH1 | Dephosphorylates CFL-1, inducing activation. |
Animals: Decreased activity in aged mice. Humans: unknown. |
Animals: Decreased activity in aged mice. Human: unknown. |
| Chemotactic Receptors | |||
| CX3CR1 | Binds to fractalkine, a neuron-secreted chemokine. Involved in baseline and directed motility and used as a marker specific of microglia. | unknown | unknown |
| P1 family | A2A involved in process retraction, A3 in process extension. | unknown | unknown |
| P2X4 | ATP/ADP receptor involved in chemotaxis. | unknown | unknown |
| P2X7 | ATP receptor; regulates IL1 secretion. |
Animals: Increased in aged mice. Humans: unknown. |
Animals: Upregulated in APPPS1 mice and associated with Aβ plaque load. Increased expression after Aβ42 intrahippocampal injections in WT mice. Decreased Aβ plaques and soluble Aβ and improved memory in APPPS1-P2X7 KO mice. Humans: Increased expression and noted in proximity to Aβ plaques. Upregulated and correlated with Aβ plaque load. |
| P2Y1 | ADP receptor involved in chemotaxis; indirectly influences CFL1 activity. | unknown |
Animals: In APPPS1 mice, its blockade improved spatial learning and memory. Humans: unknown. |
| P2Y2 | UTP receptor, regulates levels of intracellular calcium, involved in chemotaxis. | unknown |
Animals: CRND8 P2Y2-KO mice had increased soluble Aβ and plaques, and shortened lifespan. Humans: Reduced expression. |
| P2Y4 | ATP receptor involved in pinocytosis. | unknown |
Animals: unknown. Humans: No changes found. |
| P2Y6 | UDP receptor, associated with chemotaxis and phagocytosis. | unknown |
Animals: unknown. Humans: No changes observed. |
| P2Y12 | ATP/ADP receptor associated with directed motility. |
Animals: Increased expression in aged mice. Humans: unknown. |
Animals: unknown. Humans: Downregulated in microglia clustered around Aβ plaques. |