Authors: Niu, Jiahui | Iqbal, Khalid | Liu, Fei | Hu, Wen
Article Type: Research Article
Abstract: Background: Women have a two-fold higher risk than men to Alzheimer’s disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. Objective: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. Methods: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. Results: We detected no statistically significant difference in …total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190 , Ser387 , and Ser395 (Ser199 , Ser396 , and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253 , Ser387 , PHF-1 (Ser387/395 ), and Ser413 sites, which correspond to Ser262 , Ser396 , Ser396/404 , and Ser422 of human tau, respectively. Conclusion: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes. Show more
Keywords: Alzheimer’s disease, entorhinal cortex, gender, hippocampus, protein phosphorylation, tau expression, tau isoforms
DOI: 10.3233/JAD-210341
Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 855-869, 2021
Authors: Hu, Wen | Dai, Chun-Ling | Niu, Jiahui | Iqbal, Khalid
Article Type: Research Article
Abstract: Background: The triple transgenic mouse model of Alzheimer’s disease (3×Tg-AD) has gained popularity in Alzheimer’s research owing to the progressive development of both amyloid-β and tau pathologies in its brain. Prior handling-habituation, a necessary preparation procedure that reduces anxiety and stress in rodents, was seldom described in the literature involving these mice and needs to be addressed. Objective: We sought to determine whether 3×Tg-AD mice differ from B6;129 genetic control mice in terms of tameness and prior habituation to handling. Methods: We devised hand-staying and hand-boarding assays to evaluate tameness in 3×Tg-AD and B6;129 genetic control mice at 2.5, 7, …and 11.5 months of age, representing cognitively pre-symptomatic, early symptomatic and advanced symptomatic stages of the disease, respectively. We monitored the progress of handling-habituation across 8–15 daily handling sessions and assessed the animal behaviors in elevated plus maze. Results: We found that 3×Tg-AD mice were markedly tamer than age-matched control mice at the baseline. Whereas it took 2–3 days for 3×Tg-AD mice to reach the criteria for full tameness, it took an average of 7–9 days for young genetic control mice to do so. Prior handling-habituation enhanced risk assessment and coping strategy in mice in elevated plus maze. Completely handling-habituated mice exhibited comparable anxiety indices in the maze regardless of genotype and age. Conclusion: These findings collectively point to inherently heightened tameness and accelerated handling-habituation in 3×Tg-AD mice on a B6;129 genetic background. These traits should be carefully considered when behaviors are compared between 3×Tg-AD and the genetic control mice. Show more
Keywords: 3×Tg-AD, anxiety, mouse models of Alzheimer’s disease, prior handling-habituation, tameness
DOI: 10.3233/ADR-220007
Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 245-255, 2022
Authors: Fu, Qiming | Hu, Lingyao | Wu, Hongjie | Hu, Fuyuan | Hu, Wen | Chen, Jianping
Article Type: Research Article
Abstract: In the field of building equipment control, the traditional methods have some problems – instability and slow convergence. To deal with these problems, a new Sarsa-based adaptive controller, SAC (Sarsa-based adaptive controller) was proposed. Based on the model of the exchange mechanism about the building energy consumption, the proposed method with Sarsa algorithm models the exchange mechanism of the building energy consumption, and tries to find the best control policy, which can decrease the energy consumption without losing the performance of good comfort of the building occupants. Compared with the PID method, the proposed SAC has better convergence performance and …robustness. Show more
Keywords: Energy conservation, Reinforcement learning, Sarsa algorithm, adaptive controller
DOI: 10.3233/JCM-180792
Citation: Journal of Computational Methods in Sciences and Engineering, vol. 18, no. 2, pp. 329-338, 2018
Authors: PEI, Hai-yan | HU, Wen-rong | QU, Yin-bo | MU, Rui-min | LI, Xiao-cai
Article Type: Research Article
Abstract: The degradation kinetics of strains P05 and P07 and the degradation effects of mixed strain on Microcystis aeruginosa were studied. The results showed that: (1) The degradation processes of strains P05 and P07 on Microcystis aeruginosa accorded with the first-order reaction model when the range of Chl-a concentration was from 0 to 1500 μg/L. (2) The initial bacterium densities had a strong influence on the degradation velocity. The greater the initial bacterium density was, the faster the degradation was. The degradation velocity constants of P05 were 0.1913, 0.2175 and 0.3092 respectively, when bacterium densities were 4.8 × 10^5 , 4.8 …× 10^6 , 2.4 × 10^7 cells/ml. For strain P07, they were 0.1509, 0.1647 and 0.2708. The degradation velocity constant of strain P05 was higher than that of P07 when the bacterium density was under 4.8 × 10^5 cells/ml, but the constant increasing of P07 was quicker than that of P05. (3) The degradation effects of P05 and P07 strains did not antagonize. When the concentration of Chl-a was high, the degradation effects of mixed strain excelled that of any single strains. But with the decrease of the Chl-a concentration, this advantage was not clear. When the concentration was less than 180 μg/L, the degradation effects of mixed were consistent with that of strain P07. Show more
Keywords: Bacillus sp., Microcystis aeruginosa, characteristic, degradation kinetics, velocity constant
Citation: Journal of Environmental Sciences, vol. 17, no. 2, pp. 205-207, 2005
Authors: Li, Li | Hu, Wen-yong | Liu, Li-zhi | Pang, Ya-chun | Shao, Yuan-zhi
Article Type: Research Article
Abstract: Multifractal spectrum analysis of dynamic contrast enhanced (DCE) breast MR images was used to establish a new quantitative analysis method for solid tumor blood perfusion and to explore its applicability in evaluating efficacy of breast cancer chemotherapy. Five randomly selected patients suffering from newly diagnosed malignant breast nodule lesions were enrolled in this study, and four of them were treated with neoadjuvant chemotherapy. Their DCE breast MR images were collected before and after treatment. Chemotherapeutic efficacy was analyzed using international response evaluation criteria for solid tumors (RECIST). Sandbox method for statistical number density was employed to measure and calculate multifractal …spectra of DCE breast MR images with spatiotemporal characteristics. Multifractal spectral data of malignant lesions before and after chemotherapy were compared. Multifractal spectra of malignant lesions show an asymmetric bell-shape. Chemotherapy efficacy was assessed to be partial remission (PR) for three patients and their multifractal spectral width significantly increased after chemotherapy while to be stable disease (SD) for other patient and of her changed slightly. Multifractal spectral width correlates with blood-supply condition of tumor lesion before and after chemotherapy, providing a potential suitable characteristic parameter for evaluating chemotherapeutic efficacy quantitatively. Show more
Keywords: Breast cancer, magnetic resonance imaging, multifractal spectrum, image processing
DOI: 10.3233/BME-130796
Citation: Bio-Medical Materials and Engineering, vol. 24, no. 1, pp. 163-171, 2014
Authors: Hu, Wen | Tung, Yunn Chyn | Zhang, Yanchong | Liu, Fei | Iqbal, Khalid
Article Type: Research Article
Abstract: Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer’s disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation …of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2 PP2A ) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2 PP2A -PP2A-ptau pathway in tau pathology in TBI. Show more
Keywords: 3xTg-AD mice, asparaginyl endopeptidase, chronic traumatic encephalopathy, tau hyperphosphorylation, traumatic brain injury
DOI: 10.3233/JAD-180177
Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 709-722, 2018
Authors: Zhou, Ranran | Hu, Wen | Dai, Chun-Ling | Gong, Cheng-Xin | Iqbal, Khalid | Zhu, Dalong | Liu, Fei
Article Type: Research Article
Abstract: Background: Evidence from clinical studies and basic research has shown a strong correlation between Alzheimer’s disease (AD) and type 2 diabetes. Tau, a neuronal microtubule-associated protein, is hyperphosphorylated and aggregated into neurofibrillary tangles in the AD brain. However, the expression of tau in pancreas is under debate. Objective: We determined the expression of tau in mouse pancreas. Methods: We used western blots, immunoprecipitation, and immunohistochemical staining to analyze pancreatic expression of tau in mice. Results: We found that neither total tau nor phosphorylated tau was detectable in the mouse pancreas by western blots. Immunostaining with pan tau antibodies R134d and …Tau-5 revealed bright and dense varicosities in the pancreatic islets and the exocrine pancreas. These varicosities were immunoreactive to synapsin 1, a presynaptic marker which can outline autonomic nerve profiles in pancreas, exhibiting complete colocalization with tau. Importantly, endocrine cells in islets did not exhibit specific immunoreactivity to any of pan tau antibodies tested, nor did the exocrine cells. Conclusion: In the mouse pancreas, we found that tau is exclusively expressed in autonomic nerve fibers, but there is no detectable expression in endocrine cells in the islet. Show more
Keywords: Autonomic nerve fibers, islets, pancreas, tau
DOI: 10.3233/JAD-200101
Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1339-1349, 2020
Authors: Qian, Wei | Yin, Xiaomin | Hu, Wen | Shi, Jianhua | Gu, Jianlan | Grundke-Iqbal, Inge | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei
Article Type: Research Article
Abstract: Protein phosphatase 2B (PP2B) is one of the major brain phosphatases and can dephosphorylate tau at several phosphorylation sites in vitro. Previous studies that measured PP2B activity in human brain crude extracts showed that PP2B activity was either unchanged or decreased in Alzheimer's disease (AD) brain. These results led to the speculation that PP2B might regulate tau phosphorylation and that a down-regulation of PP2B might contribute to abnormal hyperphosphorylation of tau. In this study, we immunoprecipitated PP2B from brains of six AD subjects and seven postmortem- and age-matched controls and then measured the phosphatase activity. We found a three-fold increase …in PP2B activity in AD brain as compared with control brains. The activation was due to the partial cleavage of PP2B by calpain I that was activated in AD brain. The truncation of PP2B appeared to alter its intracellular distribution in the brain. In human brains, PP2B activity correlated positively, rather than negatively, to the levels of tau phosphorylation at several sites that can be dephosphorylated by PP2B in vitro. Truncation of PP2B in the frontal cortex was more than in the temporal cortex, and tau phosphorylation was also more in the frontal cortex. Taken together, these results indicate that truncation of PP2B by calpain I elevates its activity but does not counteract the abnormal hyperphosphorylation tau in AD brain. Show more
Keywords: Alzheimer's disease, calpain, hyperphosphorylation, protein phosphatase 2B, tau
DOI: 10.3233/JAD-2010-100987
Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 617-627, 2011
Authors: Wu, Ruozhen | Gu, Jianlan | Zhou, Dingwei | Tung, Yunn Chyn | Jin, Nana | Chu, Dandan | Hu, Wen | Wegiel, Jerzy | Gong, Cheng-Xin | Iqbal, Khalid | Liu, Fei
Article Type: Research Article
Abstract: Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity was quantitatively assessed by measuring RIPA buffer–insoluble …tau in HEK-293FT/tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter. Show more
Keywords: Alzheimer’s disease, gray matter, propagation of tau pathology, seeding-competent tau, white matter
DOI: 10.3233/JAD-201290
Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1647-1659, 2021
Authors: Iban-Arias, Ruth | Wang, Shu-Han | Soares Dias Portela, Ariana | Yang, Eun-Jeong | Griggs, Elizabeth | Masieri, Sibilla | Hu, Wen | Chen, Lung-Chi | Pasinetti, Giulio Maria
Article Type: Research Article
Abstract: Background: The September 11, 2001, catastrophe unleashed widespread destruction beyond the World Center (WTC), with fires and toxic gases leaving lasting impacts. First responders at Ground Zero faced prolonged exposure to hazardous particulate matter (PM), resulting in chronic health challenges. Among the multitude of health concerns, the potential association between the WTCPM and Alzheimer’s disease (AD) has emerged as an area of intense inquiry, probing the intricate interplay between environmental factors and neurodegenerative diseases. Objective: We posit that a genetic predisposition to AD in mice results in dysregulation of the gut-brain axis following chronic exposure to WTCPM. This, in turn, …may heighten the risk of AD-like symptoms in these individuals. Methods: 3xTg-AD and WT mice were intranasally administered with WTCPM collected at Ground Zero within 72 hours after the attacks. Working memory and learning and recognition memory were monitored for 4 months. Moreover, brain transcriptomic analysis and gut barrier permeability along with microbiome composition were examined. Results: Our findings underscore the deleterious effects of WTCPM on cognitive function, as well as notable alterations in brain genes associated with synaptic plasticity, pro-survival, and inflammatory signaling pathways. Complementary, chronic exposure to the WTCPM led to increased gut permeability in AD mice and altered bacteria composition and expression of functional pathways in the gut. Conclusions: Our results hint at a complex interplay between gut and brain axis, suggesting potential mechanisms through which WTCPM exposure may exacerbate cognitive decline. Identifying these pathways offers opportunities for tailored interventions to alleviate neurological effects among first responders. Show more
Keywords: Alzheimer’s disease, cognitive decline, gut microbiome, World Center particulate matter
DOI: 10.3233/JAD-240635
Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S305-S325, 2024