Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, ...and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild-type (WT) and Zfp335 knock-down (Zfp335
) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT-PCR, RNA-sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2-month-old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS-induced microglia-mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor-kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen-6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia-mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.
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•Natural dyes were in situ identified using SERS method on fibers.•Ag nanoparticles SERS substrate was prepared by laser photoreduction.•Ag dendrites SERS substrate was prepared by ...galvanic displacement.•SERS substrates had characteristics of high sensitivity and reproducibility.•Different dye species were distinguished in one archaeological fiber.
Accurate detection of natural dyes in archaeological textiles is challenging due to limited sample availability. In situ detection of fibers by surface-enhanced Raman scattering (SERS) can overcome this challenge. In this study, we present two methods for the preparation of SERS substrates based on the laser photoreduction reaction and the galvanic displacement reaction, respectively. Our results show that the substrates prepared by these methods, including 450 nm-AgNPs, Cu-based Ag, and Zn-based Ag, offer several advantages such as rapid preparation, easy handling, low cost, high sensitivity and excellent reproducibility. Using these substrates, we successfully detected anthraquinones (alizarin, purpurin), indigoids (indigotin, indirubin), and protoberberine-type dyes in archaeological textiles from the Wei and Jin Dynasties. Notably, we were able to detect both indigo and protoberberine-type dyes in one archaeological fiber. The minimally invasive, in situ analytical approach developed provides a valuable tool for analytical applications where sampling is limited to microscopic amounts.
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.
Regulation of neuroinflammation and β‐amyloid (Aβ) production are critical factors in the pathogenesis of Alzheimer's disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an ...inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock‐in mice, called APPNL−G−F mice, significantly reduced Aβ accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF‐related apoptosis‐inducing ligand, which plays an important role in microglia‐mediated NF‐κB‐dependent neuroinflammation and neuronal Aβ production by beta‐site APP cleaving enzyme 1. Furthermore, cannula‐delivered CatE inhibitors improved memory function and reduced Aβ accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and Aβ pathology.
Microglial cathepsin E involves the secretion of TRAIL, resulting in microglia‐mediated neuroinflammation and neuronal Aβ production during AD. Cannula‐delivered Cathepsin E inhibitor improves memory function and reduced neuroinflammation and Aβ production in AD mice.
Microglia are critical players in the neuroimmune system, and their involvement in Alzheimer’s disease (AD) pathogenesis is increasingly being recognized. However, whether microglia play a positive ...or negative role in AD remains largely controversial and the precise molecular targets for intervention are not well defined. This partly results from the opposing roles of microglia in AD pathology, and is mainly reflected in the microglia-neuron interaction. Microglia can prune synapses resulting in excessive synapse loss and neuronal dysfunction, but they can also promote synapse formation, enhancing neural network plasticity. Neuroimmune crosstalk accelerates microglial activation, which induces neuron death and enhances the microglial phagocytosis of β-amyloid to protect neurons. Moreover, microglia have dual opposing roles in developing the major pathological features in AD, such as amyloid deposition and blood-brain barrier permeability. This review summarizes the dual opposing role of microglia in AD from the perspective of the interaction between neurons and microglia. Additionally, current AD treatments targeting microglia and the advantages and disadvantages of developing microglia-targeted therapeutic strategies are discussed.
Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. ...Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.
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