Kynurenic acid blunts A1 astrocyte activation against neurodegeneration in HIV-associated neurocognitive disorders

• Published in: Journal of neuroinflammation Vol. 20; no. 1; p. 87
• Main Authors: Lun, Jingxian, Li, Yubin, Gao, Xuefeng, Gong, Zelong, Chen, Xiaoliang, Zou, Jinhu, Zhou, Chengxing, Huang, Yuanyuan, Zhou, Bingliang, Huang, Pengwei, Cao, Hong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.03.2023; BioMed Central; BMC
• Subjects: Acetylcholine receptors (nicotinic); alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Antibodies; Astrocytes; Astrocytes - metabolism; Care and treatment; Causes of; Cognition; Cognition disorders; Cognitive ability; Complications and side effects; Development and progression; Digital cameras; Glycoprotein gp120; Health aspects; HIV; HIV - metabolism; HIV infection; HIV Infections - complications; HIV Infections - metabolism; HIV-1 gp120; Human immunodeficiency virus; Janus kinase 2; Kynurenic acid; Kynurenic Acid - metabolism; Kynurenic Acid - pharmacology; Males; Mice; Mice, Transgenic; Neurocognitive Disorders - metabolism; Neurodegeneration; Neurotoxic astrocytes; Neurotoxicity; Stat3 protein; Testing; Transgenic animals; Transgenic mice; Tryptophan; Tryptophan - metabolism; α7nAChR; China; United Kingdom > UK; United States > US; Japan; Tryptophan; Neurotoxic astrocytes; α7nAChR; Kynurenic acid; HIV-1 gp120
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02771-4

Despite extensive astrocyte activation in patients suffering from HIV-associated neurocognitive disorders (HAND), little is known about the contribution of astrocytes to HAND neuropathology. Here, we report that the robust activation of neurotoxic astrocytes (A1 astrocytes) in the CNS promotes neuron damage and cognitive deficits in HIV-1 gp120 transgenic mice. Notably, knockout of α7 nicotinic acetylcholine receptors (α7nAChR) blunted A1 astrocyte responses, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. Furthermore, we provide evidence that Kynurenic acid (KYNA), a tryptophan metabolite with α7nAChR inhibitory properties, attenuates gp120-induced A1 astrocyte formation through the blockade of α7nAChR/JAK2/STAT3 signaling activation. Meanwhile, compared with gp120tg mice, mice fed with tryptophan showed dramatic improvement in cognitive performance, which was related to the inhibition of A1 astrocyte responses. These initial and determinant findings mark a turning point in our understanding of the role of α7nAChR in gp120-mediated A1 astrocyte activation, opening up new opportunities to control neurotoxic astrocyte generation through KYNA and tryptophan administration.