Cortical microglia exhibit a ramified shape during sleep, while they have a hyper-ramified shape during wakefulness, which is characterized by their longer processes with increased branching points. ...The microglial molecular circadian clock regulates expressions of both cathepsin S (CatS) and P2Y12 receptors in the brain with a peak at zeitgeber time 14 (2 h after beginning of the dark phase). We postulated that these two microglia-specific molecules contribute to diurnal alterations of microglial shapes and neuronal activities in the cerebral cortex. During wakefulness, CatS secreted from cortical microglia may be involved in P2Y12 receptor-dependent process extension. Secreted CatS subsequently degrades the perineuronal nets, initiating the downscaling of both spine density and synaptic strength of cortical neurons toward the beginning of sleep. The downscaling of both spine density and synaptic strength of cortical neurons during sleep could improve signal-to-noise, which would benefit memory consolidation, or allow for new learning to occur during subsequent waking. Furthermore, disruption of CatS induces the sleep disturbance and impaired social interaction in mice. Moreover, the microglial clock system disruption may also play a role in the early pathogenesis of Alzheimer's disease. The reduced expression of BMAL1 in cortical microglia caused by oligomeric amyloid β may induce the increased presence of inflammatory phenotype through a reduction in RORα, which in turn reduced IκBα and enhanced NF-κB activation.
These observations suggest that the microglial clock system disruption contribute to pathogeneses of sleep disturbance, impaired social interaction and cognitive impairment. Therefore, the growing understanding of the microglial circadian molecular clock might aid in the development of novel pharmacological interventions against both neuropsychiatric and neurodegenerative disorders.
Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated
gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion ...of the
gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double
and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that
KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no
KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that
gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (
) gene in neurological and aging mouse models of brain disorders. Mice lacking the
gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.
Highlights • Systemic exposure to LPS from Porphyromonas gingivalis induces AD-like phenotypes. • Cathepsin B is critical for inducing microglia-mediated neuroinflammation. • Cathepsin B is critical ...for inducing microglia-dependent Aβ accumulation in neurons.
Alzheimer's disease (AD) is one of the most frequently diagnosed neurodegenerative disorders worldwide and poses a major challenge for both affected individuals and their caregivers. AD is a ...progressive neurological disorder associated with high rates of brain atrophy. Despite its durable influence on human health, understanding AD has been complicated by its enigmatic and multifactorial nature. Neurofibrillary tangles and the deposition of amyloid-beta (Aβ) protein are typical pathological features and fundamental causes of cognitive impairment in AD patients. Dysbiosis of oral and gut microbiota has been reported to induce and accelerate the formation of Aβ plaques and neurofibrillary tangles. For instance, some oral microbes can spread to the brain through cranial nerves or cellular infections, which has been suggested to increase the risk of developing AD. Importantly, the interaction between intestinal microbiota and brain cells has been recognized as influencing the development of AD as well as other neurodegenerative diseases. In particular, the metabolites produced by certain intestinal microorganisms can affect the activity of microglia and further mediate neuroinflammation, which is a leading cause of neuronal necrosis and AD pathogenesis. Which pathogens and associated pathways are involved in the development and progression of AD remains to be elucidated; however, it is well-known that gut microbiota and their metabolites can affect the brain by both direct and indirect means. Understanding the specific mechanisms involved in the interaction between these pathogens and the nervous system is vital for the early intervention in AD. In this review, we aim to comprehensively discuss the possible mechanistic pathways underlying the oral-brain, the gut-brain and the oral-gut-brain associations.
Cathepsin B (CatB) leakage from the lysosome into the cytosol in senescent microglia is associated with cognitive impairment. However, whether cellular compartmental translocation of CatB is ...associated with brain aging remains unclear. In the present study, increased CatB was found in the nucleus of CatB-overexpressed microglia followed by L-leucyl-L-leucine methyl ester, a lysosome-destabilizing reagent, and in the nuclear fraction of the cortex and hippocampus from aged mice. Moreover, CatB enzymatic activity examination showed the nuclear CatB exhibited the proteolytic activity to cleave its specific substrates. The amount of sirtuin1 (Sirt1), Sirt6, Sirt7, and p-Sirt1 was decreased in the cortical lysates from aged mice, in parallel with increased expression of proinflammatory mediators, which were diminished by CatB deficiency. Furthermore, intralateral ventricle administration of microglia overexpressed CatB, and treatment with L-leucyl-L-leucine methyl ester induced cognitive impairment in middle-aged mice. These observations suggest that the increase and nucleus translocation of CatB in senescent microglia were involved in the degradation of nuclear Sirts, which induced proinflammatory responses, resulting in cognition impairment.
•Nuclear translocation of cathepsin B with aging relates to neuroinflammation.•Nuclear cathepsin B is responsible for the degradation of nuclear sirtuins during aging.•Microglial cathepsin B–mediated neuroinflammation contributes to neurodegeneration.
As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic ...inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer's disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, "dampening inflammation" through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.
The current trend for the rapid growth of the global aging population poses substantial challenges for society. The human aging process has been demonstrated to be closely associated with changes in ...gut microbiota composition, diversity, and functional features. During the first 2 years of life, the gut microbiota undergoes dramatic changes in composition and metabolic functions as it colonizes and develops in the body. Although the gut microbiota is nearly established by the age of three, it continues to mature until adulthood, when it comprises more stable and diverse microbial species. Meanwhile, as the physiological functions of the human body deteriorated with age, which may be a result of immunosenescence and "inflammaging," the guts of elderly people are generally characterized by an enrichment of pro-inflammatory microbes and a reduced abundance of beneficial species. The gut microbiota affects the development of the brain through a bidirectional communication system, called the brain-gut-microbiota (BGM) axis, and dysregulation of this communication is pivotal in aging-related cognitive impairment. Microbiota-targeted dietary interventions and the intake of probiotics/prebiotics can increase the abundance of beneficial species, boost host immunity, and prevent gut-related diseases. This review summarizes the age-related changes in the human gut microbiota based on recent research developments. Understanding these changes will likely facilitate the design of novel therapeutic strategies to achieve healthy aging.
•Rosetta captures inter-dependency of MvG parameters, reducing optimization dimensionality.•Rosetta 3 reduces uncertainties of SWCC and HCF posterior distribution.•Rosetta 3 yields constrained ...simulations of unsaturated hydrology.
Numerical simulation of unsaturated soil hydrology relies on calibrated soil hydraulic parameters, which are subject to uncertainty due to imperfect information during the inverse modelling. This study investigates the effectiveness of reducing parameter uncertainty using the recently developed Rosetta 3 pedotransfer function. The GLUE method was employed for numerical modeling using the Darcy-Richards equation under two strategies for sampling Mualem-van Genuchten (MvG) parameters: the first uses conventional random generation of MvG parameters (GLUE-random), while the second adopts Rosetta 3 to transfer soil particle composition to MvG parameter (GLUE-Rosetta). Both approaches were used for inverse modeling of 9 typical soils, each with a recommended parameter set defined as true values and associated soil moisture dynamics as observations. The posterior parameters selected with both GLUE-random and GLUE-Rosetta show an equifinality phenomenon. GLUE-random fails to provide well-constrained posterior parameters to recover the pre-defined true values, and its posterior results of soil water characteristic curve (SWCC) and soil hydraulic conductivity function (HCF) are poorly constrained. In contrast, GLUE-Rosetta significantly improves the accuracy of the inversely-estimated soil hydraulic parameters, and the ensemble of posterior SWCC and HCF also encompasses the predefined true curves. The results demonstrate the effectiveness of using Rosetta 3 to reduce the dimensionality of the optimization problem, which results in reliable estimation of soil hydraulic parameters and soil particle compositions. Moreover, GLUE-Rosetta outperforms GLUE-random in predicting soil moisture dynamics under different rainfall intensities. Overall, it is recommended to integrate Rosetta 3 with existing optimization tools to reduce the uncertainty of soil parameters and support more reliable modeling of unsaturated soil hydrology.
Eco-geotechnics for human sustainability Ng, Charles Wang Wai; Zhang, Qi; Zhou, Chao ...
Science China. Technological sciences,
12/2022, Letnik:
65, Številka:
12
Journal Article
Recenzirano
As a result of climate change and increasing engineering activities, soil-related disasters such as slope failures and sandstorms have become more frequent worldwide. These disasters have caused not ...only loss of life, but also have led to serious economic losses as well as ecological and environmental damage. To sustain mankind, a new discipline, eco-geotechnics, has rapidly become established and developed in recent years. It integrates scientific knowledge from soil mechanics, rock mechanics, ecology, biology, and atmospheric science to develop cross-disciplinary theories and carry out experiments to tackle grand world challenges such as the effects of climate change. Through the development of eco-geotechnics, various eco-friendly technologies have been developed to mitigate sandstorms and to improve the performance of earthen structures such as embankments, slopes and landfill covers. This state-of-the-art review introduces and discusses the important advances in the field of eco-geotechnics, covering theoretical developments, laboratory testing, centrifuge modelling, field monitoring and engineering applications. Finally, the research gaps and future needs of eco-geotechnics are highlighted and discussed.
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