Complement C3 From Astrocytes Plays Significant Roles in Sustained Activation of Microglia and Cognitive Dysfunctions Triggered by Systemic Inflammation After Laparotomy in Adult Male Mice.

Aberrant activation of complement cascades plays an important role in the progress of neurological disorders. Complement C3, the central complement component, has been implicated in synaptic loss and cognitive impairment. Recent study has shown that wound injury-induced systemic inflammation can trigger the increase of C3 in the brain. Our previous studies have demonstrated that laparotomy-triggered systemic inflammation could induce neuroinflammation and cognitive dysfunctions. Furthermore, sustained activation of microglia was observed even 14 days after laparotomy, while most of cytokines had returned to basal levels rapidly at the earlier time point. Although we have demonstrated that anti-inflammatory intervention successfully attenuated cognitive dysfunction by preventing increase of cytokines and activation of microglia, how sustained activation of microglia and cognitive dysfunction occur is still a mystery. In this study, we investigated the role of C3 in mediating activation of microglia and cognitive dysfunction by using laparotomy in adult male mouse only as the experimental model of systemic inflammation and AAV9-C3shRNA. Our data observed that laparotomy induced neurotoxic reactive astrocytes with an increase of C3 in the hippocampus. Furthermore, inhibition of C3 by AAV9-C3shRNA prevented synaptic engulfment by microglia and attenuated cognitive dysfunctions after laparotomy. Inhibition of C3 did not modulate activation of astrocytes and expression of various cytokines. Current findings demonstrated that C3 plays significant roles in sustained activation of microglia and cognitive dysfunctions, which suggests that C3 is the valuable molecule target to attenuate in neurological conditions characterised by neuroinflammation and cognitive dysfunction.

Downregulation of the glucose transporter GLUT 1 in the cerebral microvasculature contributes to postoperative neurocognitive disorders in aged mice.

INTRODUCTION: Glucose transporter 1 (GLUT1) is essential for glucose transport into the brain and is predominantly expressed in the cerebral microvasculature. Downregulation of GLUT1 precedes the development of cognitive impairment in neurodegenerative conditions. Surgical trauma induces blood-brain barrier (BBB) disruption, neuroinflammation, neuronal mitochondria dysfunction, and acute cognitive impairment. We hypothesized that surgery reduces the expression of GLUT1 in the BBB that in turn disrupts its integrity and contributes to metabolic dysregulation in the brain that culminates in postoperative cognitive impairment. METHODOLOGY: Using an abdominal surgery model in aged WT mice, we assessed the perioperative changes in cognitive performance, tight junction proteins expression, GLUT1 expression, and the associated metabolic effects in the hippocampus. Thereafter, we evaluated the effects of these parameters in aged mice with conditional overexpression of GLUT1, and then again in aged mice with conditional overexpression of GLUT1 with or without prior exposure to the GLUT1 inhibitor ST-31. RESULTS: We showed a significant decline in cognitive performance, along with GLUT1 reduction and diminished glucose metabolism, especially in the ATP level in the postoperative mice compared with controls. Overexpression of GLUT1 expression alleviated postoperative cognitive decline and improved metabolic profiles, especially in adenosine, but did not directly restore ATP generation to control levels. GLUT1 inhibition ameliorated the postoperative beneficial effects of GLUT1 overexpression. CONCLUSIONS: Surgery-induced GLUT1 reduction significantly contributes to postoperative cognitive deficits in aged mice by affecting glucose metabolism in the brain. It indicates the potential of targeting GLUT1 to ameliorate perioperative neurocognitive disorders.

IL-1ß and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer's disease.

BACKGROUND: Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer's disease. With advancing age, the progressive increase in the body's pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer's disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases. METHODS: To examine the impacts of periodontitis on the onset and progression of Alzheimer's disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer's disease, interleukin 1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice. RESULTS: Here, we show that IL-1ß and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer's disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer's disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer's disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice. CONCLUSIONS: Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer's disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer's disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer's disease.

Clinically relevant small-molecule promotes nerve repair and visual function recovery.

Adult mammalian injured axons regenerate over short-distance in the peripheral nervous system (PNS) while the axons in the central nervous system (CNS) are unable to regrow after injury. Here, we demonstrated that Lycium barbarum polysaccharides (LBP), purified from Wolfberry, accelerated long-distance axon regeneration after severe peripheral nerve injury (PNI) and optic nerve crush (ONC). LBP not only promoted intrinsic growth capacity of injured neurons and function recovery after severe PNI, but also induced robust retinal ganglion cell (RGC) survival and axon regeneration after ONC. By using LBP gene expression profile signatures to query a Connectivity map database, we identified a Food and Drug Administration (FDA)-approved small-molecule glycopyrrolate, which promoted PNS axon regeneration, RGC survival and sustained CNS axon regeneration, increased neural firing in the superior colliculus, and enhanced visual target re-innervations by regenerating RGC axons leading to a partial restoration of visual function after ONC. Our study provides insights into repurposing of FDA-approved small molecule for nerve repair and function recovery.

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders.

Background: The incidence of perioperative neurocognitive disorders (PNDs) is reportedly higher in older patients. Mitochondrial and synaptic dysfunctions have consistently been demonstrated in models of aging and neurodegenerative diseases; nonetheless, their role in PND is not well understood. Methods: The Morris water maze and elevated plus maze tests were used to assess the learning and memory abilities of both C57BL/6 and 3×Tg-AD mice of different ages (8 and 18 months). PND was induced by laparotomy in C57BL/6 mice and 3×Tg-AD mice (8 months old). Markers associated with neuroinflammation, mitochondrial function, synaptic function, and autophagy were assessed postoperatively. The roles of protein kinase C (PKC) and double-stranded RNA-dependent protein kinase (PKR) were further demonstrated by using PKC-sensitive inhibitor bisindolylmaleimide X (BIMX) or PKR-/- mice. Results: Significant cognitive impairment was accompanied by mitochondrial dysfunction and autophagy inactivation in both aged C57BL/6 and 3×Tg-AD mice. Laparotomy induced a significant neuroinflammatory response and synaptic protein loss in the hippocampus. Cognitive and neuropathological changes induced by aging or laparotomy were further exacerbated in 3×Tg-AD mice. Deficits in postoperative cognition, hippocampal mitochondria, autophagy, and synapse were significantly attenuated after pharmacological inhibition of PKC or genetic deletion of PKR. Conclusions: Our findings suggest similar pathogenic features in aging, Alzheimer's disease, and PND, including altered mitochondrial homeostasis and autophagy dysregulation. In addition, laparotomy may exacerbate cognitive deficits associated with distinct neuronal inflammation, mitochondrial dysfunction, and neuronal loss independent of genetic background. The dysregulation of PKC/PKR activity may participate in the pathogenesis of these neurodegenerative diseases.

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aß) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aß plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aß plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aß plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aß plaques were located in the amygdala, and the cerebellum; but no Aß plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aß plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aß deposition in the brain and its inter-regional correlation. This suggests an association between Aß plaque deposition and specific brain regions in AD pathogenesis.

Leukocyte invasion of the brain after peripheral trauma in zebrafish (Danio rerio).

Despite well-known systemic immune reactions in peripheral trauma, little is known about their roles in posttraumatic neurological disorders, such as anxiety, sickness, and cognitive impairment. Leukocyte invasion of the brain, a common denominator of systemic inflammation, is involved in neurological disorders that occur in peripheral inflammatory diseases, whereas the influences of peripheral leukocytes on the brain after peripheral trauma remain largely unclear. In this study, we found that leukocytes, largely macrophages, transiently invaded the brain of zebrafish larvae after peripheral trauma through vasculature-independent migration, which was a part of the systemic inflammation and was mediated by interleukin-1b (il1b). Notably, myeloid cells in the brain that consist of microglia and invading macrophages were implicated in posttraumatic anxiety-like behaviors, such as hyperactivity (restlessness) and thigmotaxis (avoidance), while a reduction in systemic inflammation or myeloid cells can rescue these behaviors. In addition, invading leukocytes together with microglia were found to be responsible for the clearance of apoptotic cells in the brain; however, they also removed the nonapoptotic cells, which suggested that phagocytes have dual roles in the brain after peripheral trauma. More importantly, a category of conserved proteins between zebrafish and humans or rodents that has been featured in systemic inflammation and neurological disorders was determined in the zebrafish brain after peripheral trauma, which supported that zebrafish is a translational model of posttraumatic neurological disorders. These findings depicted leukocyte invasion of the brain during systemic inflammation after peripheral trauma and its influences on the brain through il1b-dependent mechanisms.

Prehabilitative resistance exercise reduces neuroinflammation and improves mitochondrial health in aged mice with perioperative neurocognitive disorders.

BACKGROUND: Postoperative neurocognitive dysfunction remains a significant problem in vulnerable groups such as the elderly. While experimental data regarding its possible pathogenic mechanisms accumulate, therapeutic options for this disorder are limited. In this study, we evaluated the neuroprotective effect of a period of preconditioning resistant training on aged mice undergoing abdominal surgery. Further, we examined the underlying mechanisms from the perspective of neuroinflammatory state and synaptic plasticity in the hippocampus. METHODS: 18-month-old C57BL/6N mice were trained for 5 weeks using a ladder-climbing protocol with progressively increasing weight loading. Preoperative baseline body parameters, cognitive performance and neuroinflammatory states were assessed and compared between sedentary and trained groups of 9-month-old and 18-month-old mice. To access the neuroprotective effect of resistance training on postoperative aged mice, both sedentary and trained mice were subjected to a laparotomy under 3% sevoflurane anesthesia. Cognitive performance on postoperative day 14, hippocampal neuroinflammation, mitochondrial dysfunction and synaptic plasticity were examined and compared during groups. RESULTS: 18-month-old mice have increased body weight, higher peripheral and central inflammatory status, reduction in muscle strength and cognitive performance compared with middle-aged 9-month-old mice, which were improved by resistance exercise. In the laparotomy group, prehabilitative resistant exercise improved cognitive performance and synaptic plasticity, reduced inflammatory factors and glial cells activation after surgery. Furthermore, resistance exercise activated hippocampal PGC-1α/BDNF/Akt/GSK-3ß signaling and improved mitochondrial biogenesis, as well as ameliorated mitochondrial dynamics in postoperative-aged mice. CONCLUSIONS: Resistance exercise reduced risk factors for perioperative neurocognitive disorders such as increased body weight, elevated inflammatory markers, and pre-existing cognitive impairment. Accordantly, preoperative resistance exercise improved surgery-induced adverse effects including cognitive impairment, synaptic deficit and neuroinflammation, possibly by facilitate mitochondrial health through the PGC1-a/BDNF pathway.

Sevoflurane Induces Neurotoxicity in the Animal Model with Alzheimer's Disease Neuropathology via Modulating Glutamate Transporter and Neuronal Apoptosis.

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer's disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background.

Linking circadian rhythms to microbiome-gut-brain axis in aging-associated neurodegenerative diseases.

Emerging evidence suggests that both disruption of circadian rhythms and gut dysbiosis are closely related to aging-associated neurodegenerative diseases. Over the last decade, the microbiota-gut-brain axis has been an emerging field and revolutionized studies in pathology, diagnosis, and treatment of neurological disorders. Crosstalk between the brain and gut microbiota can be accomplished via the endocrine, immune, and nervous system. Recent studies have shown that the composition and diurnal oscillation of gut microbiota are influenced by host circadian rhythms. This provides a new perspective for investigating the microbiome-gut-brain axis. We aim to review current understanding and research on the dynamic interaction between circadian rhythms and the microbiome-gut-brain axis. Furthermore, we will address the possible neurodegenerative disease contribution through circadian rhythms and microbiome-gut-brain axis crosstalk.

Sigesbeckia orientalis L. Derived Active Fraction Ameliorates Perioperative Neurocognitive Disorders Through Alleviating Hippocampal Neuroinflammation.

Neuroinflammation is closely related to the pathogenesis of perioperative neurocognitive disorders (PNDs), which is characterized by the activation of microglia, inflammatory pathways and the release of inflammatory mediators. Sigesbeckia orientalis L. (SO) is a traditional Chinese medicine which demonstrates anti-inflammatory activities in different models. In this study, we aim to isolate the active fraction from the extract of SO with higher anti-inflammatory potential and confirm if the selected fraction exerts neuroprotection against the development of PND in an animal model. Moreover, the components in the selected fraction would be determined by UPLC-PDA analysis. Three fractions were prepared by column chromatography packed with three different macroporous resins. Anti-inflammatory activities of prepared fractions were accessed in microglial BV2 cultures by nitric oxide release, gene expression of inflammatory cytokines and activation of inflammatory JNK and NF-kB pathway molecules. Our results demonstrated that the fraction prepared from D101 macroporous resin (D101 fraction) exhibited a more potent anti-neuroinflammatory effect. The neuroprotective effect of D101 fraction was further examined in postoperative mice. Our results showed that surgery-induced cognitive dysfunction was attenuated by the D101 fraction treatment. This fraction also reduced microglial activation, inflammatory cytokines and inhibiting JNK and NF-kB pathway molecules in the hippocampus. In addition, surgery induced dendritic spine loss while D101 fraction ameliorated the spine loss in the hippocampus. For safety concerns, anti-thrombotic effect was examined by tail bleeding assay and no significant change of the bleeding pattern was found. UPLC-PDA analysis indicated that flavonoids (rutin, isochlorogenic acid A, isochlorogenic acid C) and terpenoid (darutoside) were the most important components in the D101 fraction. Our results support a therapeutic, as well as the translational potential for D101 fraction in ameliorating postoperative neuroinflammation and subsequent PND in the clinical setting without increasing bleeding tendencies.

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration.

The functions of the complement system to both innate and adaptive immunity through opsonization, cell lysis, and inflammatory activities are well known. In contrast, the role of complement in the central nervous system (CNS) which extends beyond immunity, is only beginning to be recognized as important to neurodevelopment and neurodegeneration. In addition to protecting the brain against invasive pathogens, appropriate activation of the complement system is pivotal to the maintenance of normal brain function. Moreover, overactivation or dysregulation may cause synaptic dysfunction and promote excessive pro-inflammatory responses. Recent studies have provided insights into the various responses of complement components in different neurological diseases and the regulatory mechanisms involved in their pathophysiology, as well as a glimpse into targeting complement factors as a potential therapeutic modality. However, there remain significant knowledge gaps in the relationship between the complement system and different brain disorders. This review summarizes recent key findings regarding the role of different components of the complement system in health and pathology of the CNS and discusses the therapeutic potential of anti-complement strategies for the treatment of neurodegenerative conditions.

The pathogenic effects of particulate matter on neurodegeneration: a review.

The increasing amount of particulate matter (PM) in the ambient air is a pressing public health issue globally. Epidemiological studies involving data from millions of patients or volunteers have associated PM with increased risk of dementia and Alzheimer's disease in the elderly and cognitive dysfunction and neurodegenerative pathology across all age groups, suggesting that PM may be a risk factor for neurodegenerative diseases. Neurodegenerative diseases affect an increasing population in this aging society, putting a heavy burden on economics and family. Therefore, understanding the mechanism by which PM contributes to neurodegeneration is essential to develop effective interventions. Evidence in human and animal studies suggested that PM induced neurodenegerative-like pathology including neurotoxicity, neuroinflammation, oxidative stress, and damage in blood-brain barrier and neurovascular units, which may contribute to the increased risk of neurodegeneration. Interestingly, antagonizing oxidative stress alleviated the neurotoxicity of PM, which may underlie the essential role of oxidative stress in PM's potential effect in neurodegeneration. This review summarized up-to-date epidemiological and experimental studies on the pathogenic role of PM in neurodegenerative diseases and discussed the possible underlying mechanisms.

The role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative diseases.

Recent research into meningeal lymphatics has revealed a never-before appreciated role of type II innate lymphoid cells (ILC2s) in modulating neuroinflammation in the central nervous system (CNS). To date, the role of ILC2-mediated inflammation in the periphery has been well studied. However, the exact distribution of ILC2s in the CNS and therefore their putative role in modulating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and major depressive disorder (MDD) remain highly elusive. Here, we review the current evidence of ILC2-mediated modulation of neuroinflammatory cues (i.e., IL-33, IL-25, IL-5, IL-13, IL-10, TNFα, and CXCL16-CXCR6) within the CNS, highlight the distribution of ILC2s in both the periphery and CNS, and discuss some challenges associated with cell type-specific targeting that are important for therapeutics. A comprehensive understanding of the roles of ILC2s in mediating and responding to inflammatory cues may provide valuable insight into potential therapeutic strategies for many dementia-related disorders.

Applications of adeno-associated virus vector-mediated gene delivery for neurodegenerative diseases and psychiatric diseases: Progress, advances, and challenges.

Neurodegeneration is the most common disease in the elderly population due to its slowly progressive nature of neuronal deterioration, eventually leading to executive dysfunction. The pathological markers of neurological disorders are relatively well-established, however, detailed molecular mechanisms of progression and therapeutic targets are needed to develop novel treatments in human patients. Treating known therapeutic targets of neurological diseases has been aided by recent advancements in adeno-associated virus (AAV) technology. AAVs are known for their low-immunogenicity, blood-brain barrier (BBB) penetrating ability, selective neuronal tropism, stable transgene expression, and pleiotropy. In addition, the usage of AAVs has enormous potential to be optimized. Therefore, AAV can be a powerful tool used to uncover the underlying pathophysiology of neurological disorders and to increase the success in human gene therapy. This review summarizes different optimization approaches of AAV vectors with their current applications in disease modeling, neural tracing and gene therapy, hence exploring progressive mechanisms of neurodegenerative diseases as well as effective therapy. Lastly, this review discusses the limitations and future perspectives of the AAV-mediated transgene delivery system.

Impact of unilateral ureteral obstruction on cognition and neurodegeneration.

INTRODUCTION: Cognitive impairment is a common complication in chronic kidney disease (CKD) patients. Currently, limited types of animal models are available for studying cognitive impairment in CKD. We used unilateral ureteral obstruction (UUO) in mice as an animal model to study the cognitive changes and related pathology under prolonged renal impairment METHODS: UUO was performed in 8-week-old male C57BL/6 N mice with double-ligation of their left ureter. A sham group was subjected to the same experimental procedure without ureteral obstruction. Cognitive and behavioral tests were performed to examine potential changes in cognition and behavior at 2, 4 and 12 weeks after surgery. Sera were collected, and kidneys and brains were harvested for the detection of systemic inflammation markers and neurodegenerative changes. RESULTS: These mice displayed weak performance in the novel object recognition test, Y-maze test, and puzzle box test compared to the sham group. Reductions in synaptic proteins such as synapsin-1, synaptophysin, synaptotagmin, PSD95, NMDAR2B and AMPAR were confirmed by western blot analysis. Histological examination revealed elevated levels of Nrf2 and 8-hydroxyguanosine, and hyperphosphorylation of tau in the hippocampus. UUO mice also had increased levels of C-reactive protein (CRP) and TNF-α. CONCLUSIONS: We characterized the cognitive and neuropathological changes in UUO mice. The results show that this mouse model can be used to further study cognitive changes related to chronic renal impairment.

Preservation of Retinal Function Through Synaptic Stabilization in Alzheimer's Disease Model Mouse Retina by Lycium Barbarum Extracts.

In Alzheimer's disease (AD), amyloid ß deposition-induced hippocampal synaptic dysfunction generally begins prior to neuronal degeneration and memory impairment. Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In this study, we aimed to investigate the effects of LBE on the synapse loss in AD through the avenue of the retina in a triple transgenic mouse model of AD (3xTg-AD). We fed 3xTg-AD mice with low (200 mg/kg) or high (2 g/kg) dose hydrophilic LBE daily for 2 months from the starting age of 4- or 6-month-old. For those started at 6 month age, at 1 month (though not 2 months) after starting treatment, mice given high dose LBE showed a significant increase of a wave and b wave in scotopic ERG. After 2 months of treatment with high dose LBE, calpain-2, calpain-5, and the oxidative RNA marker 8-OHG were downregulated, and presynaptic densities in the inner plexiform layer but not the outer plexiform layer of the retina were significantly increased, suggesting the presynaptic structure of retina was preserved. Our results indicate that LBE feeding may preserve synapse stability in the retina of 3xTg-AD mice, probably by decreasing both oxidative stress and intracellular calcium influx. Thus, LBE might have potential as a neuroprotectant for AD through synapse preservation.