Microglia-Astrocyte Communication in Alzheimer's Disease

Abstract

Microglia and astrocytes are regarded as active participants in the central nervous system under various neuropathological conditions, including Alzheimer's disease (AD). Both microglia and astrocyte activation have been reported to occur with a spatially and temporarily distinct pattern. Acting as a double-edged sword, glia-mediated neuroinflammation may be both detrimental and beneficial to the brain. In a variety of neuropathologies, microglia are activated before astrocytes, which facilitates astrocyte activation. Yet reactive astrocytes can also prevent the activation of adjacent microglia in addition to helping them become activated. Studies describe changes in the genetic profile as well as cellular and molecular responses of these two types of glial cells that contribute to dysfunctional immune crosstalk in AD. In this paper, we construct current knowledge of microglia-astrocyte communication, highlighting the multifaceted functions of microglia and astrocytes and their role in AD. A thorough comprehension of microglia-astrocyte communication could hasten the creation of novel AD treatment approaches.

Keywords: Alzheimer’s disease; astrocyte; cellular crosstalk; microglia; neuroinflammation.

Fig. 1

Illustrations of microglia and astrocyte polarization. Activated microglia are often classified as M1 or M2 phenotypes as displayed in the upper half of Fig. 1. Resting microglia polarize to the M1 phenotype and produce pro-inflammatory substances such as TNFα, IL1β, IL6, IL12, IL18, NO, and ROS, when LPS and IFN-γ are present. In contrast, IL4 and IL13 stimulation causes M2 polarization, which increases the secretion of anti-inflammatory substances such as TGF-β, VEGF, IGF1, BDNF, NGF, IL4, IL10, and IL13. Additionally, M2 microglia could promote the inhibition of M1 microglia by the anti-inflammatory cytokine IL10. Activated astrocytes are usually divided into A1 and A2 phenotypes as depicted in the lower half of Figure 1. Astrocytes may transform into different reactive astrocyte phenotypes depending on the stimulus. The M1 microglia’s production of the pro-inflammatory cytokines IL1α, TNFα, and C1q causes the A1 neurotoxic phenotype and encourages the secretion of TNFα, IL1β, IL6, and ROS. Meanwhile, IL1β, IL6, and NFIA trigger the A2 phenotypic change with neuroprotective effects that increase anti-inflammatory molecules TGF-β, IL4, and IL10. BDNF, brain-derived neurotrophic factor; C1q, complement component 1q; IFN-γ, interferon-gamma; IGF1, insulin-like growth factor 1; IL, interleukin; LPS, lipopolysaccharide; NFIA, nuclear factor IA; NGF, nerve growth factor; NO, nitric oxide; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta 1; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor.

Fig. 2

The interplay between microglia and astrocytes. DAMP/PAMP signaling activates microglia via TLR receptors, which then regulate the phenotypes of astrocytes, which can range from neurotoxic to neuroprotective. Microglia and astrocytes can have a direct effect on each other via numerous molecules as demonstrated in Fig. 2. C1q, Complement component 1q; CCL2, C-C motif ligand 2; CLCF1, Cardiotrophin-like cytokine factor 1; CXCL10, C-X-C, motif chemokine ligand 10; IFN-γ, Interferon gamma; IL, Interleukin; NFIA, Nuclear factor IA; PTX3, Pentraxin 3; TGF-β, Transforming growth factor-beta 1; TNFα, Tumor necrosis factor alpha.

Fig. 3

Molecular conversation between microglia and astrocytes. The signaling pathway between microglia and astrocytes is listed here briefly (modified from Li et al. [215]). ATP, Adenosine triphosphate; C1q, Complement component 1q; C1qR, C1q: Complement component 1q receptor; C3aR, C3a receptor; CCR, C-C chemokine receptor; CXCL12, C-X-C motif chemokine ligand 12; CXCR4, C-X-C chemokine receptor type 4; GDNF, Glial cell line-derived neurotrophic factor; IL, Interleukin; LCN2, Lipocalin 2; MCP1, Monocyte chemoattractant protein 1; ORM2, Orosomucoid 2; P2Y, metabotropic; ST2, Suppressor of tumorigenicity 2; TNF, Tumor necrosis factor; TrkB, Tropomyosin-related kinase B.