Fig. 2

Molecular and cellular effects of A1-like C3 + astrocytes. Neurotoxic reactive astrocytes upregulation of the pro-inflammatory NF-κB signaling pathway results in increased complement component expression (C1r, C1s, C3, C4) and synaptic damage [43, 74, 75, 117, 142]. Other pro-inflammatory mediators expressed by A1-like astrocytes include IL-1β, TNF-α, and IL-6 [63]. Hyperphosphorylation and activation of the STAT pathway has been reported in inflammatory reactive astrocytes associated with injury response [144]. Inhibition of the anti-inflammatory PI3K-Akt pathway results in reduced TGF-β expression, and downregulation of synaptogenic factors and neurotrophic signals, including BDNF and GDNF, contribute to synapse loss and apoptosis [129, 135]. Increased glycolytic functions and secretion of astrocyte-derived exosomes containing increased concentrations of C3 have been identified in neuropathology-associated reactive astrocytes, specifically in the context of AD [34, 145]. Changes in expression of AQP4, resulting in dysregulated water homeostasis at the BBB, are another hallmark of A1-like astrocytes [60]. Other factors secreted by A1-like neurotoxic reactive astrocytes with unidentified functions include Serpina3n, Lipocalin, and CLIC1, with several neurotoxic factors yet to be identified [83, 129]. Chemoattractive signals for T lymphocytes, such as CXCL10, and neutrophils, such as CINC-1 and CINC-2, are also produced by neurotoxic astrocytes, potentially contributing to immune cell infiltration and establishing a pro-inflammatory environment [21, 41, 57, 75, 121]. Secreted C3 binds to the C3aR receptor on local neurons, resulting in subsequent dysregulation of intraneuronal Ca²⁺ homeostasis and excitotoxicity [74]