FGFR3 drives Aß-induced tau uptake.

The amyloid cascade hypothesis suggests that amyloid beta (Aß) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aß contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aß induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aß accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aß-induced tau uptake in AD.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-ß. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-ß, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

Amyloid-ß activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway.

Neuroinflammation is considered one of major factors in the pathogenesis of Alzheimer's disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro-inflammatory response of immune cells. However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear. Here, we show that amyloid-ß activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK. Deactivated AMPK induces metabolic dysregulation, mitochondrial fragmentation, and reactive oxygen species formation, leading to the activation of the NLRP3 inflammasome. In addition, flufenamic acid (FA), a member of non-steroidal anti-inflammatory drugs, was found to effectively inhibit activation of the microglial NLRP3 inflammasome by regulating Syk and AMPK. Importantly, FA has marked therapeutic effects on major AD pathologies and memory function in vivo in microglia-dependent way. All together, these findings demonstrate the molecular mechanism of microglial NLRP3 inflammasome activation by amyloid-ß, which acts as an important mediator of neuroinflammation. Also, we suggest that repurposing of FA for inhibiting microglial activation of the NLRP3 inflammasome is a potential treatment for AD.

Community detection in dynamic networks via adaptive label propagation.

An adaptive label propagation algorithm (ALPA) is proposed to detect and monitor communities in dynamic networks. Unlike the traditional methods by re-computing the whole community decomposition after each modification of the network, ALPA takes into account the information of historical communities and updates its solution according to the network modifications via a local label propagation process, which generally affects only a small portion of the network. This makes it respond to network changes at low computational cost. The effectiveness of ALPA has been tested on both synthetic and real-world networks, which shows that it can successfully identify and track dynamic communities. Moreover, ALPA could detect communities with high quality and accuracy compared to other methods. Therefore, being low-complexity and parameter-free, ALPA is a scalable and promising solution for some real-world applications of community detection in dynamic networks.

Multifractality and Network Analysis of Phase Transition.

Many models and real complex systems possess critical thresholds at which the systems shift dramatically from one sate to another. The discovery of early-warnings in the vicinity of critical points are of great importance to estimate how far the systems are away from the critical states. Multifractal Detrended Fluctuation analysis (MF-DFA) and visibility graph method have been employed to investigate the multifractal and geometrical properties of the magnetization time series of the two-dimensional Ising model. Multifractality of the time series near the critical point has been uncovered from the generalized Hurst exponents and singularity spectrum. Both long-term correlation and broad probability density function are identified to be the sources of multifractality. Heterogeneous nature of the networks constructed from magnetization time series have validated the fractal properties. Evolution of the topological quantities of the visibility graph, along with the variation of multifractality, serve as new early-warnings of phase transition. Those methods and results may provide new insights about the analysis of phase transition problems and can be used as early-warnings for a variety of complex systems.

Multi-resolution community detection in massive networks.

Aiming at improving the efficiency and accuracy of community detection in complex networks, we proposed a new algorithm, which is based on the idea that communities could be detected from subnetworks by comparing the internal and external cohesion of each subnetwork. In our method, similar nodes are firstly gathered into meta-communities, which are then decided to be retained or merged through a multilevel label propagation process, until all of them meet our community criterion. Our algorithm requires neither any priori information of communities nor optimization of any objective function. Experimental results on both synthetic and real-world networks show that, our algorithm performs quite well and runs extremely fast, compared with several other popular algorithms. By tuning a resolution parameter, we can also observe communities at different scales, so this could reveal the hierarchical structure of the network. To further explore the effectiveness of our method, we applied it to the E-Coli transcriptional regulatory network, and found that all the identified modules have strong structural and functional coherence.

Protoporphyrin IX catalyzed hydrogen peroxide to generate singlet oxygen.

AIM: To study the role of protoporphyrin IX (pPIX) in mitochondrial metabolism of hydrogen peroxide (H2O2). METHODS: O2 (-) specific fluorescent markers DMA (9,10-dimerthylanthracence) and SOSG (Singlet Oxygen Sensor Green reagent) were used for measurement of singlet oxygen ((1)O2). Catalyzing conversion of H2O2 into (1)O2 by pPIX was monitored in vitro under varied H2O2 content, temperature, and PH value in the reaction. Ex vivo mitochondrial model was used to analyze effects of ferrochelatase (FECH) and high energy X-rays on this catalytic reaction. RESULTS: In complete dark, measurable (1)O2 was generated when 1.5 mM of H2O2 was incubated with 24 µM of pPIX H2O2 at 37°C for 3 hours. Mitochondrial yield of H2O2 was 0.11±0.03 nmole/mg/min. Mitochondrial FECH significantly improve the catalytic ability of pPIX converting H2O2 into (1)O2. At presence of high-energy X-ray, incubation of 14.4 µM of pPIX with 0.54 µM of H2O2 also generated (1)O2, during which the fluorescence density of 1.05 µM of DMA decreased by 41.5% (P < 0.05). This conversion was not observed when pPIX was replaced with structurally similar hematoporphyrin. CONCLUSION: pPIX can catalyze conversion of H2O2 into (1)O2.

Assessment of antidiabetogenic potential of fermented soybean extracts in streptozotocin-induced diabetic rat.

Most of the available drugs for the treatment of diabetes mellitus (DM) produce detrimental side effects, which has prompted an ongoing search for plant with the antidiabetic potential. The present study investigated the effect of soybean extracts fermented with Bacillus subtilis MORI, fermented soybean extracts (BTD-1) was investigated in streptozotocin (STZ)-induced diabetic rats. The possible effects of BTD-1 against hyperglycemia and free radical-mediated oxidative stress was investigated by assaying the plasma glucose level and the activity of enzymatic antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). A significant increase in the levels of both plasma glucose and reactive oxygen species (ROS) was observed in the diabetic rats when compared to normal control group. After administration of BTD-1 (500 and 1000 mg/kg/day), the elevated plasma glucose level was significantly reduced while the plasma insulin level and the activities of SOD, GSH-Px, CAT and MDA were significantly increased. The results suggest that administration of BTD-1 can inhibit hyperglycemia and free radical-mediated oxidative stress. The administration of BTD-1 also inhibited the contractile response by norepinephrine (10(-10)-10(-5) M) in the presence of endothelium, and caused significant relaxation by carbachol (10(-8)-10(-5) M) in rat aorta. These findings indicate that BTD-1 improves vascular functions on STZ-induced diabetic rats. Therefore, subchronic administration of BTD-1 could prevent the functional changes in vascular reactivity in STZ-induced diabetic rats. The collective findings support that administration of BTD-1 may prevent some diabetes-related changes in vascular reactivity directly and/or indirectly due to its hypoglycaemic effect and inhibition of production of ROS.

Generation of CD2(+)CD8(+) NK Cells from c-kit(+) Bone Marrow Cells in Porcine.

Natural killer (NK) cells provide one of the initial barriers of cellular host defense against pathogens, in particular intracellular pathogens. Because bone marrow-derived hematopoietic stem cells (HSCs), lymphoid protenitors, can give rise to NK cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that porcine c-kit(+) bone marrow cells (c-kit(+) BM cells) develop into NK cells in vitro in the presence of various cytokines [interleukin (IL)-2, IL-7, IL-15, IL-21, stem cell factor (SCF), and fms-like tyrosine kinase-3 ligand (FLT3L)]. Adding hydrocortisone (HDC) and stromal cells greatly increases the frequency of c-kit(+) BM cells that give rise to CD2(+)CD8(+) NK cells. Also, intracellular levels of perforin, granzyme B, and NKG2D were determined by RT-PCR and western blotting analysis. It was found that of perforin, granzyme B, and NKG2D levels significantly were increased in cytokine-stimulated c-kit(+) BM cells than those of controls. And, we compared the ability of the cytotoxicity of CD2(+)CD8(+) NK cells differentiated by cytokines from c-kit(+) BM cells against K562 target cells for 28 days. Cytokines-induced NK cells as effector cells were incubated with K562 cells as target in a ratio of 100:1 for 4 h once a week. In results, CD2(+)CD8(+) NK cells induced by cytokines and stromal cells showed a significantly increased cytotoxicity 21 days later. Whereas, our results indicated that c-kit(+) BM cells not pretreated with cytokines have lower levels of cytotoxicity. Taken together, this study suggests that cytokines-induced NK cells from porcine c-kit(+) BM cells may be used as adoptive transfer therapy if the known obstacles to xenografting (e.g. immune and non-immune problems) were overcome in the future.