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Possible biochemical changes in hepatic and renal functions due to exposure of petrol vapour were assessed in twenty (20) petrol station attendants in Owerri, Imo State, Nigeria. A corresponding twenty healthy subjects who were not exposed to petrol or its vapour were used as controls. The results showed a significant increase in the (p

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The wall shear stress (WSS) exerted by blood flowing through microvascular capillaries is an established driver of new blood vessel growth, or angiogenesis. Such adaptations are central to many physiological processes in both health and disease, yet three-dimensional (3D) WSS characteristics in real angiogenic microvascular networks are largely unknown. This marks a major knowledge gap because angiogenesis, naturally, is a 3D process. To advance current understanding, we model 3D red blood cells (RBCs) flowing through rat angiogenic microvascular networks using state-of-the-art simulation. The high-resolution fluid dynamics reveal 3D WSS patterns occurring at sub-endothelial cell (EC) scales that derive from distinct angiogenic morphologies, including microvascular loops and vessel tortuosity. We identify the existence of WSS hot and cold spots caused by angiogenic surface shapes and RBCs, and notably enhancement of low WSS regions by RBCs. Spatiotemporal characteristics further reveal how fluctuations follow timescales of RBC "footprints." Altogether, this work provides a new conceptual framework for understanding how shear stress might regulate EC dynamics in vivo., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Amyloid β protein (Aβ) and tau, the two main proteins implicated in causing Alzheimer's disease (AD), are posited to trigger synaptic dysfunction long before significant synaptic loss occurs in vulnerable circuits. Whereas soluble Aβ aggregates from AD brain are well recognized potent synaptotoxins, less is known about the synaptotoxicity of soluble tau from AD or other tauopathy patient brains. Minimally manipulated patient-derived aqueous brain extracts contain the more diffusible native forms of these proteins. Here, we explore how intracerebral injection of Aβ and tau present in such aqueous extracts of patient brain contribute to disruption of synaptic plasticity in the CA1 area of the male rat hippocampus. Aqueous extracts of certain AD brains acutely inhibited long-term potentiation (LTP) of synaptic transmission in a manner that required both Aβ and tau. Tau-containing aqueous extracts of a brain from a patient with Pick's disease (PiD) also impaired LTP, and diffusible tau from either AD or PiD brain lowered the threshold for AD brain Aβ to inhibit LTP. Remarkably, the disruption of LTP persisted for at least 2 weeks after a single injection. These findings support a critical role for diffusible tau in causing rapid onset, persistent synaptic plasticity deficits, and promoting Aβ-mediated synaptic dysfunction. SIGNIFICANCE STATEMENT The microtubule-associated protein tau forms relatively insoluble fibrillar deposits in the brains of people with neurodegenerative diseases including Alzheimer's and Pick's diseases. More soluble aggregates of disease-associated tau may diffuse between cells and could cause damage to synapses in vulnerable circuits. We prepared aqueous extracts of diseased cerebral cortex and tested their ability to interfere with synaptic function in the brains of live rats. Tau in these extracts rapidly and persistently disrupted synaptic plasticity and facilitated impairments caused by amyloid β protein, the other major pathologic protein in Alzheimer's disease. These findings show that certain diffusible forms of tau can mediate synaptic dysfunction and may be a target for therapy., Competing Interests: D.M.W. is an employee of Biogen. M.S.P. and A.B. are employees and shareholders of AstraZeneca. R.W. and J.A.P. are employees of Transpharmation Ireland. All the other authors declare no competing financial interests., (Copyright © 2023 the authors.)

We previously showed that death-associated protein kinase 1 (DAPK1) expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer's disease. In addition, depression is a risk factor for developing Alzheimer's disease, as well as an early clinical manifestation of Alzheimer's disease. Meanwhile, cognitive dysfunction is a distinctive feature of major depressive disorder. Therefore, DAPK1 may be related to cognitive dysfunction in major depressive disorder. In this study, we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic, mild, unpredictable stressors. We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area, and tau was hyperphosphorylated at Thr231, Ser262, and Ser396 in these mice. Furthermore, DAPK1 shifted from axonal expression to overexpression on the cell membrane. Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction. These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder., Competing Interests: None

Peri-urban vegetable field plays an essential role in providing vegetables for local residents. Because of its particularity, it is affected by both industrial and agricultural activities which have led to the accumulations of heavy metal in soil. So far, information on heavy metal pollution status, spatial features, and human health risks in peri-urban vegetable areas across China is still scarce. To fill this gap, we systematically compiled soil and vegetable data collected from 123 articles published between 2010 and 2022 at a national level. The pollution status of heavy metals (i.e., cadmium (Cd), mercury (Hg), arsenic (As), lead (Pb), chromium (Cr), copper (Cu), nickel (Ni), and zinc (Zn)) in peri-urban vegetable soils and vegetables were investigated. To evaluate the levels of heavy metal pollution in soil and human health risks, the geoaccumulation index (Igeo) and target hazard quotient (HQ) were calculated. The results showed that mean concentrations of Cd, Hg, As, Pb, Cr, Cu, Ni, and Zn in peri-urban vegetable soils were 0.50, 0.53, 12.03, 41.97, 55.56, 37.69, 28.55, and 75.38 mg kg -1 , respectively. The main pollutants in peri-urban vegetable soil were Cd and Hg, and 85.25% and 92.86% of the soil samples had I geo > 1, respectively. The mean I geo values of this regions followed the order of northwest > central > south > north > east > southwest > northeast for Cd and northeast > northwest > north > southwest > east > central > south for Hg. The mean Cd, Hg, As, Pb, Cr, Cu, Ni, and Zn concentrations in vegetables were 0.30, 0.26, 0.37, 0.54, 1.17, 6.17, 1.96, and 18.56 mg kg -1 , respectively. Approximately 87.01% (Cd), 71.43% (Hg), 20% (As), 65.15% (Pb), 27.08% (Cr) of the vegetable samples exceeded the safety requirement values. The vegetables grown in central, northwest, and northern China accumulated much more heavy metals than those grown in other regions. As the HQ values for adults, 53.25% (Cd), 71.43% (Hg), 84.00% (As), and 58.33% (Cr) of the sampled vegetables were higher than 1. For children, the HQ values were higher than 1 for 66.23% (Cd), 73.81% (Hg), 86.00% (As), and 87.50% (Cr) of the sampled vegetables. The findings of this study demonstrate that the situation of heavy metal pollution in peri-urban vegetable areas across China are not optimistic and residents who consume the vegetables are at high risk of health issues. To ensure soil quality and human health, strategies should be taken to guide vegetable production and remedy soil pollution in peri-urban areas with the rapidly urbanizing China., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-β or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions., Competing Interests: None

The gap between in vitro and in vivo assays has inspired biomimetic model development. Tissue engineered models that attempt to mimic the complexity of microvascular networks have emerged as tools for investigating cell-cell and cell-environment interactions that may be not easily viewed in vivo . A key challenge in model development, however, is determining how to recreate the multi-cell/system functional complexity of a real network environment that integrates endothelial cells, smooth muscle cells, vascular pericytes, lymphatics, nerves, fluid flow, extracellular matrix, and inflammatory cells. The objective of this mini-review is to overview the recent evolution of popular biomimetic modeling approaches for investigating microvascular dynamics. A specific focus will highlight the engineering design requirements needed to match physiological function and the potential for top-down tissue culture methods that maintain complexity. Overall, examples of physiological validation, basic science discoveries, and therapeutic evaluation studies will emphasize the value of tissue culture models and biomimetic model development approaches that fill the gap between in vitro and in vivo assays and guide how vascular biologists and physiologists might think about the microcirculation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lampejo, Hu, Lucas, Lomel, Nguyen, Dominguez, Ren, Huang and Murfee.)

Soluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ 1-42 . Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD., (© 2022. The Author(s).)

The value-added utilization of tobacco stalk lignin is the key to the development of tobacco stalk resources. However, the serious heterogeneity is the bottleneck for making full use of tobacco stalk lignin. Based on this, lignin was separated from tobacco stalk through hydrothermal assisted dilute alkali pretreatment. Subsequently, the tobacco stalk alkaline lignin was fractionated into five uniform lignin components by sequential solvent fractionation. Advanced spectral technologies (FT-IR, NMR, and GPC) were used to reveal the effects of hydrothermal assisted dilute alkali pretreatment and solvent fractionation on the structural features of tobacco stalk lignin. The lignin fractions extracted with n -butanol and ethanol had low molecular weight and high phenolic hydroxyl content, thus exhibiting superior chemical reactivity and antioxidant capacity. By contrast, the lignin fraction extracted with dioxane had high molecular weight and low reactivity, nevertheless, the high residual carbon rate made it suitable as a precursor for preparing carbon materials. In general, hydrothermal assisted dilute alkali pretreatment was proved to be an efficient method to separate lignin from tobacco stalk, and the application of sequential solvent fractionation to prepare lignin fractions with homogeneous structural features has specific application prospect., Competing Interests: ZL, ZW, SG, YT, XL, NH, QY, and XZ were employed by the companies China Tobacco Hubei Industrial Co., Ltd. and Hubei Xinye Reconstituted Tobacco Development Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Wang, Gao, Tong, Le, Hu, Yan, Zhou, He and Wang.)

Synaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer's disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer's disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer's disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer's disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer's disease., (© 2021. The Author(s).)

To date, although there are many studies investigating the toxicity of heavy metal to plant, little research exists in the seasonal freeze-thaw (FT) regions where FT cycles often happen during the plant growing process. To reveal the adaptive mechanisms of plants to the combination stresses of cadmium (Cd) and FT, the Cd accumulation, subcellular distribution, chemical forms, and antioxidant enzyme activity (peroxidase (POD)) were investigated in spinach (Spinacia oleracea L.) growing under different soil Cd levels (i.e., 0.10 mg Cd kg -1 soil (low), 1.21 mg Cd kg -1 soil (medium), and 2.57 mg Cd kg -1 soil (high)). Compared to the non-freeze-thaw (NFT) treatments, higher Cd concentrations in the root and lower translocation factors from root to leaf were found for the plants experiencing FT cycles. FT significantly decreased the Cd concentrations in the leaves under the low- and medium-Cd treatments, while similar values were found for the high-Cd treatments. Generally, FT could decrease the concentrations and proportions of Cd stored in the cell wall and soluble fractions and increase them in the organelle fractions for the medium- and high-Cd treatments, while opposite tendency was found for the low-Cd treatments. Moreover, larger Cd amounts in the inorganic and water-soluble forms were found for the low- and medium-Cd treated plants under FT, while lower values were found for the high-Cd treatments. Additionally, POD, which presented higher activities at the low- and medium-Cd treatments and lower activities at the high-Cd treatments under FT, were also significantly influenced by the Cd × FT interaction. This study indicated that FT could significantly change the accumulations of Cd in plant, and it provided a new insight into the Cd accumulation by plants in the seasonal FT region., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head (ONFH) in systemic lupus erythematosus (SLE). Some gene loci such as complement C3d receptor 2 ( CR2 ), nitric oxide synthase 3 ( NOS3 ), collagen type II alpha 1 chain ( COL2A1 ), protein tyrosine phosphatase non-receptor type 22 ( PTPN22 ), and transient receptor potential cation channel subfamily V member 4 ( TRPV4 ) were reported to be involved in this process., Aim: To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations (SNVs) in these five genes., Methods: SNVs in the CR2 , NOS3 , COL2A1 , PTPN22 , and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH. Burrows-wheeler aligner was used to align the sequencing reads to hg19, and GATK and Varscan programs were used to perform SNV calling. PolyPhen-2, SIFT, and MutationTaster were used to assess the functional effects of non-synonymous SNVs., Results: Six of the 49 patients were confirmed to have low frequency SNVs, including one patient with SNVs in NOS3 (exon 6: c.814G>A: p.E272K and exon 7: c.814G>A: p.E272K.), four in COL2A1 (rs41263847: exon 29: c.1913C>T: p.T638I, exon 28: c.1706C>T: p.T569I, and rs371445823: exon 8: c.580G>A: p.A194T, exon 7: c.373G>A: p.A125T), and one in CR2 (rs45573035: exon 2: c.200C>G: p.T67S)., Conclusion: The onset of ONFH in SLE might be associated with the identified SNVs in NOS3, COL2A1 , and CR2 ., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

How endogenously produced soluble amyloid ß-protein (Aß) affects synaptic plasticity in vulnerable circuits should provide insight into early Alzheimer's disease pathophysiology. McGill-R-Thy1-APP transgenic rats, modeling Alzheimer's disease amyloidosis, exhibit an age-dependent soluble Aß-mediated impairment of the induction of long-term potentiation (LTP) by 200 Hz conditioning stimulation at apical CA3-to-CA1 synapses. Here, we investigated if synaptic weakening at these synapses in the form of activity-dependent persistent reversal (depotentiation) of LTP is also altered in pre-plaque rats in vivo . In freely behaving transgenic rats strong, 400 Hz, conditioning stimulation induced stable LTP that was NMDA receptor- and voltage-gated Ca 2+ channel-dependent. Surprisingly, the ability of novelty exploration to induce depotentiation of 400 Hz-induced LTP was impaired in an Aß-dependent manner in the freely behaving transgenic rats. Moreover, at apical synapses, low frequency conditioning stimulation (1 Hz) did not trigger depotentiation in anaesthetized transgenic rats, with an age-dependence similar to the LTP deficit. In contrast, at basal synapses neither LTP, induced by 100 or 200 Hz, nor novelty exploration-induced depotentiation was impaired in the freely behaving transgenic rats. These findings indicate that activity-dependent weakening, as well as strengthening, is impaired in a synapse- and age-dependent manner in this model of early Alzheimer's disease amyloidosis.

The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo.

Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer's disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo. This relatively sparse synaptic LTD requires both the ion channel function and GluN2B subunit of the NMDA receptor but, in contrast to electrically induced LTD, is not facilitated by boosting endogenous muscarinic acetylcholine or metabotropic glutamate 5 receptor activation. Although in the absence of Aß, there is no evidence of hippocampal LTD asymmetry, in the presence of Aß, the induction of LTD is preferentially enhanced in the left hippocampus in an mGluR5-dependent manner. This circuit-selective disruption of synaptic plasticity by Aß provides a route to understanding the development of aberrant brain lateralization in AD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer's disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer's disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrP(C)-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

Alzheimer's disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aβ) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aβ, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aβ aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.

Background: T-helper (Th) 22 is involved in the pathogenesis of inflammatory diseases. The roles of Th22 cells in the pathophysiological of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) remain unsettled. So we examined the frequencies of Th22 cells, Th17 cells and Th1 cells in peripheral blood (PB) from patients with AS and patients with RA compared with both healthy controls as well as patients with osteoarthritis., Design and Methods: We studied 32 AS patients, 20 RA patients, 10 OA patients and 20 healthy controls. The expression of IL-22, IL-17 and IFN-γ were examined in AS, RA, OA patients and healthy controls by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay., Results: Th22 cells, Th17 cells and interleukin-22 were significantly elevated in AS and RA patients compared with OA patients and healthy controls. Moreover, Th22 cells showed positive correlation with Th17 cells as well as interleukin-22 in AS and RA patients. However, positive correlation between IL-22 and Th17 cells was only found in AS patients not in RA patients. In addition, the percentages of both Th22 cells and Th17 cells correlated positively with disease activity only in RA patients not in AS patients., Conclusions: The frequencies of both Th22 cells and Th17 cells were elevated in PB from patients with AS and patients with RA. These findings suggest that Th22 cells and Th17 cells may be implicated in the pathogenesis of AS and RA, and Th22 cells and Th17 cells may be reasonable cellular targets for therapeutic intervention.

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.

Long before the onset of clinical Alzheimer's disease non-fibrillar, soluble assembly states of amyloid-beta (Abeta) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimer's disease are vascular, impairment of cerebral blood flow by soluble Abeta has been proposed to be critical in triggering these early changes. However, it is not known if soluble Abeta can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimer's disease. Here we developed a new method to simultaneously assess the ability of soluble Abeta to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Abeta(40) dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10-42 pmol) comparable to natural Abeta, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Abeta(40), the more vasculotropic Abeta produced by people with familial hemorrhagic stroke of the Dutch type (Abeta(40)E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Abeta(42), even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Abeta species of early Alzheimer's disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics.

Peripheral nerve injury leads to the establishment of a novel synaptic connection between afferent Abeta-fiber and lamina II neurons in spinal dorsal horn, which is hypothesized to underlie mechanical allodynia. However, how the novel synapses transmit nociceptive information is poorly understood. In the present study, the role of protein tyrosine kinases (PTKs) in Abeta-fiber-evoked excitatory postsynaptic currents (EPSCs) recorded in lamina II neurons in transverse spinal cord slices of rats was investigated using the whole-cell patch-clamp recording technique. In the slices from sciatic nerve transection (SNT) rats, genistein (50 microM), a broad-spectrum PTKs inhibitor, or PP2 (20 microM), a selective Src family tyrosine kinase inhibitor, significantly reduced the amplitude of Abeta-fiber EPSCs. In sham-operated rats, however, Abeta-fiber EPSCs were insensitive to genistein and PP2. The N-methyl-D-aspartate (NMDA) receptor antagonist AP-V (50 microM) suppressed Abeta-fiber EPSCs in slices from SNT rats but not from sham-operated rats. Following nerve injury, the slow inward currents elicited by bath application of NMDA (100 muM) significantly increased at -70 mV. In SNT rats, genistein and PP2 reduced Abeta-fiber-evoked EPSCs mediated by NMDA receptor; however, genistein produced little effect on Abeta-fiber EPSCs mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These data suggested that PTKs, especially Src family members, participated in Abeta-fiber-evoked synaptic transmission following sciatic nerve injury via potentiation of NMDA receptor function.

Long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn may be relevant to pathological pain. Our previous work has shown that the late phase of the spinal LTP is protein synthesis-dependent. Considerable evidence has accumulated that dopamine D1/D5 receptors are important for late-phase LTP in hippocampus. In this study, the role of D1/D5 receptors in LTP of C-fiber-evoked field potentials in spinal dorsal horn was evaluated in urethan-anesthetized Sprague-Dawley rats. We found the following. 1) Spinal application of SKF 38393, a D1/D5 receptor agonist, induced a slowly developed LTP of C-fiber-evoked field potentials, lasting for >10 h, and the effect was blocked by the D1/D5 antagonist SCH 23390, whereas a D2 receptor agonist (quinpirole) induced depression of C-fiber responses, lasting for 2 h. 2) The potentiation produced by D1/D5 receptor agonist occluded the late phase but not the early phase of the spinal LTP produced by tetanic stimulation. 3) SCH 23390 selectively depressed the late-phase LTP, when applied 40 min before tetanic stimulation. 4) The D1/D5 agonist-induced potentiation is blocked by the protein synthesis inhibitor anisomycin. 5) Activation of protein kinase A by spinal application of 8-Br-cAMP also induced spinal LTP, and the action occluded the potentiation induced by the D1/D5 receptor agonist. These results suggest that the spinal D1/D5 receptors participate in the protein synthesis-dependent late-phase LTP of C-fiber-evoked field potentials in spinal dorsal horn through the cAMP signaling pathway.

Previous studies have demonstrated that in the hippocampus the maintenance of long-term potentiation (LTP) requires de novo protein synthesis. To investigate the role of protein synthesis in the maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn, which may be relevant to hyperalgesia, protein synthesis inhibitor (either cycloheximide or anisomycin) was applied locally to the recording segments of spinal cord in anesthetized rats, 30 min prior to tetanic stimulation to the sciatic nerve. We found that both cycloheximide and anisomycin selectively inhibited late-phase maintenance of the spinal LTP but affected neither LTP induction nor baseline responses of C-fiber evoked field potentials. In the presence of cycloheximide, LTP of C-fiber evoked field potentials was 281.5 +/- 16.5% (n = 6) of baseline 1 h after tetanic stimulation and the potentiation significantly decreased to 235.5 +/- 18.5% at 145 min after tetanic stimulation (P < 0.05). Afterward, LTP of C-fiber evoked field potentials decreased continuously and at 270 min after tetanic stimulation reached 130.8 +/- 18.0%, which was no longer different from baseline (P > 0.05). Spinal application of anisomycin at 30 min before tetanic stimulation yielded similar results (n = 6). These results suggest that protein synthesis may be crucial for the late-phase maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn.