Fig. 3

mtDNA-cGAS-STING signal pathway and neuroinflammation in AD. A. In the AD brain, the neurotoxic effects of primary pathological proteins, such as Aβ plaques and neurofibrillary tangles. The overwhelmed mitochondria of injured neurons release mtDNA into the extramitochondrial space, activating immune cells and forming a neuroinflammatory microenvironment in the CNS. B. The activation of the mtDNA-cGAS-STING pathway in the brain of AD. Firstly, various adverse factors in AD, such as Aβ plaques, hyperphosphorylated tau, ROS, and aging, stimulate the release of mtDNA from mitochondria in neurons. This mtDNA, along with AD pathological proteins, initiates the cGAS-STING pathway through multiple mechanisms. Secondly, cGAMP spreads through gap junctions in neurons and various glial cells, leading to the release of a series of cytokines by activated glial cells, and modulating neuronal inflammation. Ultimately, the activation of cGAS-STING would lead to complex outcomes. Various cell types in the brain play a role in the activation of this pathway, which, on one hand, can alleviate brain inflammation to some extent, while, on the other hand, its excessive activation forms a widespread neuroinflammatory network, exacerbating brain damage and promoting disease progression