The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.

Peripheral Inflammatory Biomarkers of Methamphetamine Withdrawal Patients Based on the Neuro-Inflammation Hypothesis: The Possible Improvement Effect of Exercise

Methamphetamine (MA) induced addiction and neuroinflammation has been implicated. Based on the neuroinflammation hypothesis, this study aims to investigate how exercise influences the craving of patients in MA withdrawal, and explore the mechanism of peripheral inflammation. A total of 90 patients in MA withdrawal were recruited. No difference was noted in the number of years of drug use and the frequency of drug use among patients, and the withdrawal time was within 2 months. The subjects were grouped based on the degree of craving induced by the cues: non-craving control group (NCC group), craving control group (CC group), and craving exercise group (CE group). The CE group was subjected to aerobic combined resistance training. Then, the ELISA method was used to detect plasma IL-6, TNF-α, and IL-1β concentrations; Visual Analog Scale (VAS) measurement of cue-induced cravings under Virtual Reality (VR) exposure (VR-VAS) and the Desires for Drug Questionnaire (DDQ) were used to assess cravings. Consequently, plasma IL-6, TNF-α, IL-1β, levels, and the VR-VAS and DDQ scores of MA withdrawal patients were significantly reduced after exercise. This study confirmed that 8 weeks of incremental load aerobic combined with resistance training reduces peripheral inflammation and significantly reduces the level of craving for MA.

Jak2 Inhibitor AG490 Improved Poststroke Central and Peripheral Inflammation and Metabolic Abnormalities in a Rat Model of Ischemic Stroke

Poststroke hyperglycemia and inflammation have been implicated in the pathogenesis of stroke. Janus Kinase 2 (Jak2), a catalytic signaling component for cytokine receptors such as Interleukin-6 (IL-6), has inflammatory and metabolic properties. This study aimed to investigate the roles of Jak2 in poststroke inflammation and metabolic abnormality in a rat model of permanent cerebral ischemia. Pretreatment with Jak2 inhibitor AG490 ameliorated neurological deficit, brain infarction, edema, oxidative stress, inflammation, caspase-3 activation, and Zonula Occludens-1 (ZO-1) reduction. Moreover, in injured cortical tissues, Tumor Necrosis Factor-α, IL-1β, and IL-6 levels were reduced with concurrent decreased NF-κB p65 phosphorylation, Signal Transducers and Activators of Transcription 3 phosphorylation, Ubiquitin Protein Ligase E3 Component N-Recognin 1 expression, and Matrix Metalloproteinase activity. In the in vitro study on bEnd.3 endothelial cells, AG490 diminished IL-6-induced endothelial barrier disruption by decreasing ZO-1 decline. Metabolically, administration of AG490 lowered fasting glucose, with improvements in glucose intolerance, plasma-free fatty acids, and plasma C Reactive Proteins. In conclusion, AG490 improved the inflammation and oxidative stress of neuronal, hepatic, and muscle tissues of stroke rats as well as impairing insulin signaling in the liver and skeletal muscles. Therefore, Jak2 blockades may have benefits for combating poststroke central and peripheral inflammation, and metabolic abnormalities.

RhANP attenuates endotoxin-derived cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota–brain axis

Background Atrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment. Methods LPS (5 mg/kg) was given intraperitoneally to mice. Recombinant human ANP (rhANP) (1.0 mg/kg) was injected intravenously 24 h before and/or 10 min after LPS injection. Subdiaphragmatic vagotomy (SDV) was performed 14 days before LPS injection or 28 days before fecal microbiota transplantation (FMT). ANA-12 (0.5 mg/kg) was administrated intraperitoneally 30 min prior to rhANP treatment. Results LPS (5.0 mg/kg) induced remarkable splenomegaly and an increase in the plasma cytokines at 24 h after LPS injection. There were positive correlations between spleen weight and plasma cytokines levels. LPS also led to increased protein levels of ionized calcium-binding adaptor molecule (iba)-1, cytokines and inducible nitric oxide synthase (iNOS) in the hippocampus. LPS impaired the natural and learned behavior, as demonstrated by an increase in the latency to eat the food in the buried food test and a decrease in the number of entries and duration in the novel arm in the Y maze test. Combined prophylactic and therapeutic treatment with rhANP reversed LPS-induced splenomegaly, hippocampal and peripheral inflammation as well as cognitive impairment. However, rhANP could not further enhance the protective effects of SDV on hippocampal and peripheral inflammation. We further found that PGF mice transplanted with fecal bacteria from rhANP-treated endotoxemia mice alleviated the decreased protein levels of hippocampal polyclonal phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotrophic factor (BDNF) and cognitive impairment, which was abolished by SDV. Moreover, TrkB/BDNF signaling inhibitor ANA-12 abolished the improving effects of rhANP on LPS-induced cognitive impairment. Conclusions Our results suggest that rhANP could mitigate LPS-induced hippocampal inflammation and cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota–brain axis.