Tau Mediates Cognitive Resilience in Alzheimer's Disease Patients By Activating The CGAS-IFN Pathway in Microglia
Apr 25, 2023
Alzheimer's disease (AD), the most common form of late-onset dementia, has a long asymptomatic period during which amyloid-beta plaques and tau aggregates are progressively deposited, eventually entering a symptomatic period with cognitive decline and other symptoms. Although the mechanism of this transformation is unknown, it is consistent with alterations in the innate immune response, blood vessels, and metabolism. Single nucleotide polymorphisms in innate immune genes are associated with susceptibility to sporadic late-onset AD, suggesting that poor innate immune responses contribute to cognitive decline.
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Antiviral response pathways are upregulated in AD and regulate microglial disease responses, including immune activation/suppression, and synapse pruning in aging, and neurodegenerative diseases. Cyclic GMP-AMP synthetase (cGAS) is a major antiviral DNA sensor that binds double-stranded DNA (dsDNA) and catalyzes the formation of cyclic GMP-AMP (cGAMP), thereby activating the stimulator of interferon genes (STING). STING recruits TANK-binding kinase 1 (TBK1) and promotes TBK1 autophosphorylation to activate type-1 interferon (IFN-I) expression.
Studies have shown that the cGAS-STING pathway drives deleterious IFN-I activation in multiple neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). cGAS-STING activation exacerbates amyloid-β pathology in 5xFAD mice. Although tau activates the cGAS-STING pathway and increases NF-κB signaling in microglia in vitro, how cGAS activation predisposes the brain to tau-associated cognitive decline remains unknown.
On April 24, 2023, Li Gan's team at Weill Cornell Medicine (co-authors as Joe C. Udeochu1, Sadaf Amin, and Yige Huang) published the article Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience in Nature Neuroscience. In this study, the authors explored the activation of the cGAS-STING-IFN signaling pathway in microglia from mice with P301S tau pathology and from human AD patients.
Using behavioral, electrophysiological, and single-nuclear (sn) RNA-sequencing approaches, we demonstrate that Cgas knockdown is potently protective against effects associated with synaptic and cognitive deficits induced by the MEF2C transcriptional network, MEF2C is a gene associated with cognitive resilience. Single-cell nuclear (sn) RNA-sequencing analysis of AD patients also revealed dysregulation of the IFN-I gene in microglia and the MEF2C transcriptional network in neurons.
How is the cGAS-STING pathway activated in microglia? As a sensor of cytosolic DNA, cGAS may be activated by mitochondrial or nuclear DNA leakage. The researchers found that after tau is phagocytized, it exists in mitochondria and lysosomes, and tau fibers can trigger the release of mtDNA into the cytoplasm. By depleting mtDNA, the tau-induced interferon response is attenuated in a dose-dependent manner with mtDNA concentration.
Through the Morris water maze test, the researchers found that Cgas knockout significantly improved the spatial learning and memory abilities of P301S mice. Tau-induced defects in hippocampal synaptic plasticity are associated with memory loss associated with tau pathology. Measuring long-term potentiation (LTP) induced by Theta burst stimulation (TBS) in the hippocampus revealed late LTP deficiency in P301S mice, which was rescued by the knockout of the Cgas gene. Further measuring PSD-95, a marker of excitatory postsynaptic terminals in the CA1 region of the hippocampus, the researchers found that knockdown of the Cgas gene ameliorated tau pathology-induced PSD-95 reduction in CA1 pyramidal neurons.
Using snRNA-seq, we found that the protection conferred by cGAS inactivation was associated with an enhanced transcriptional network of the cognitive resilience gene MEF2C. MEF2C is an AD risk gene, and variation within the MEF2C locus is associated with differences in human intelligence. In snRNA-seq analysis, MEF2C was one of the most upregulated genes in differential gene expression (DEG) after Cgas knockdown. Both gas knockout and the cGAS pharmacological inhibitor TDI-6570 induced MEF2C target gene expression in tau mouse neurons, suggesting that upregulated MEF2C underlies the cognitive protective mechanism.
Among MEF2C target genes, Cgas knockdown significantly altered gene networks involved in axon guidance, dendrite outgrowth, synapse maintenance, calcium signaling/homeostasis, and neuronal excitability in both excitatory and inhibitory hippocampal neurons. Using the STING agonist DMXAA, we demonstrated that activation of the STING-IFN axis downregulates the expression of Mef2c and its target genes in neurons through interferon-alpha/beta receptor 1 (IFNAR1).
In conclusion, this study links hyperactive cGAS-IFN antiviral responses to reduced MEF2C-related cognitive resilience, confirming that malign innate immune responses lead to increased susceptibility to cognitive decline. In disease, cGAS overactivation promotes microglial IFN-I responses, reduces neuronal MEF2C transcriptional activity, and leads to loss of cognitive resilience. cGAS knockdown attenuates microglial IFN-I responses and enhances neuronal MEF2C transcriptional networks and cognitive resilience associated with tau pathology. Inhibition of cGAS with TDI-6570 enhanced MEF2C target genes and restored synaptic integrity and memory, supporting the therapeutic potential of targeting the cGAS-MEF2C axis to enhance cognitive resilience against AD-related dementia.
what is the mechanism of Cistanche's anti-Alzheimer's disease effect
There is some emerging research suggesting that Cistanche may have anti-Alzheimer's disease effects through its ability to increase brain-derived neurotrophic factor (BDNF), reduce oxidative stress, and promote neuroprotection.
One study published in the Journal of Ethnopharmacology found that treatment with Cistanche tubulosa extracts improved memory and cognitive function in mice with Alzheimer's disease-like symptoms by increasing levels of BDNF in the hippocampus, a brain region essential for learning and memory. BDNF is a protein that supports the growth, survival, and differentiation of neurons and is known to decline in individuals with Alzheimer's disease.
Other studies have suggested that Cistanche may protect the brain against damage from oxidative stress by scavenging free radicals and boosting antioxidant defenses. It may also have neuroprotective effects by regulating inflammation, inhibiting apoptosis (programmed cell death), and enhancing mitochondrial function.
