Modeling the innate inflammatory cGAS/STING pathway: sexually dimorphic effects on microglia and cognition in obesity and prediabetes

IntroductionThe prevalence of obesity, prediabetes, and diabetes continues to grow worldwide. These metabolic dysfunctions predispose individuals to neurodegenerative diseases and cognitive impairment, including dementias such as Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). The innate inflammatory cGAS/STING pathway plays a pivotal role in metabolic dysfunction and is an emerging target of interest in multiple neurodegenerative diseases, including AD/ADRD. Therefore, our goal was to establish a murine model to specifically target the cGAS/STING pathway to study obesity- and prediabetes-induced cognitive impairment.MethodsWe performed two pilot studies in cGAS knockout (cGAS-/-) male and female mice designed to characterize basic metabolic and inflammatory phenotypes and examine the impact of high-fat diet (HFD) on metabolic, inflammatory, and cognitive parameters.ResultscGAS-/- mice displayed normal metabolic profiles and retained the ability to respond to inflammatory stimuli, as indicated by an increase in plasma inflammatory cytokine production in response to lipopolysaccharide injection. HFD feeding caused expected increases in body weight and decreases in glucose tolerance, although onset was accelerated in females versus males. While HFD did not increase plasma or hippocampal inflammatory cytokine production, it did alter microglial morphology to a state indicative of activation, particularly in female cGAS-/- mice. However, HFD negatively impacted cognitive outcomes in male, but not female animals.DiscussionCollectively, these results suggest that cGAS-/- mice display sexually dimorphic responses to HFD, possibly based on differences in microglial morphology and cognition

Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease

Abstract The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate‐ and glucose‐induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate‐treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance

Image_4_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Image_2_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

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Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Image_5_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Image_9_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Table_1_cGAS/STING and innate brain inflammation following acute high-fat feeding.xlsx

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Image_7_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p

Image_1_cGAS/STING and innate brain inflammation following acute high-fat feeding.tif

Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer’s disease and Alzheimer’s disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.</p