Innate immunity in brain aging and neurodegeneration

Inflammation has been linked to normal aging and gradual decline in various cellular processes [1].However, the mechanism and the pathways responsible for inflammation-mediated aging, especially in the brain, remain elusive.A new study by Gullen et al [2] shows that a molecular signaling pathway, consisting of two main proteins, cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), plays a critical role in driving chronic inflammation and functional decline during aging.It was previously known that activation of the cGAS/STING pathway triggers an innate immune response in defense against viral and bacterial infections [3][4][5][6].Now, by using the small molecule inhibitor H-151 [6] and RNA interference experiments in cultures and tissue samples, Gullen et al [2] demonstrate that the inflammatory response of senescent cells is suppressed after blockade of STING.These manipulations also protect against inflammation and activation of inflammatory genes [2].Currently, the signaling pathway(s) involved in inflammation-mediated brain aging and associated cognitive decline is only poorly understood [7,8,9].The work by Gullen et al [2] helps fill this gap in knowledge since it shows that STING inhibition not only reduces levels of immune-related signature genes in the brains of aged mice, but also improves both, spatial memory (assessed in the Morris water maze test) and associative memory (contextual-fear-conditioning test).Moreover, the authors report that STING inhibition protects against the loss of neurons in the CA1 region of the hippocampus and increases local levels of synaptophysin [10], a marker for synaptic activity.Further insight into the role of STING signaling was also provided in the work by Gullen et al [2] who found that the age-dependent increase of phosphorylated TBK1 (pTBK1), the major kinase responsible for signal transduction downstream of STING [11], is attenuated by inhibition of STING.Microglial activation and microgliosis is widely implicated in age-related neurodegenerative diseases [12,13,14].In their new study, the authors [2] observed that inhibition of STING activity results in an attenuation of the differential expression of genes in the hippocampi of young and aged mice, namely, those involved in innate immunity such as genes related to type I interferon (IFN) signaling and microglial function.They also found increased phosphorylated STING activity in hippocampal microglia from old mice, implying that a role for STING in orchestrating innate immune activation in the aging brain.Adding support to this, Gullen et al [2] found that blockade of STING mitigates microgliosis and immunoreactive astrocytes in the hippocampi of aged mice.This interpretation was supported by their finding that aged Sting1 -/-mice simultaneously display reduced microglial accumulation and increased neuron density in the hippocampal area (Fig. 1).At another level, the authors [2] used two mouse models to demonstrate that direct activation of cGAS is sufficient to generate transcriptional clusters that correspond to previously-identified subsets; these included disease-associated microglia (DAM), IFNassociated and neurodegenerative microglial states that are associated with ageing and neurodegenerative conditions [15,16].Previous studies observed that cells in each of these states show strong upregulation of genes associated with IFN, DAM and neurodegenerative signatures [15,17,18].To understand the link between cGAS and STING, it should be noted that earlier studies showed that mitochondrial DNA (mtDNA)