NADPH oxidase as a therapeutic target in Alzheimer\u27s disease

At present, available treatments for Alzheimer\u27s disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both β amyloid (Aβ) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS). NADPH oxidase is a multi-subunit enzyme complex responsible for the production of both extracellular and intracellular ROS by microglia. Importantly, NADPH oxidase expression is upregulated in AD and is an essential component of microglia-mediated Aβ neurotoxicity. Activation of microglial NADPH oxidase causes neurotoxicity through two mechanisms: 1) extracellular ROS produced by microglia are directly toxic to neurons; 2) intracellular ROS function as a signaling mechanism in microglia to amplify the production of several pro-inflammatory and neurotoxic cytokines (for example, tumor necrosis factor-α, prostaglandin E2, and interleukin-1β). The following review describes how targeting NADPH oxidase can reduce a broad spectrum of toxic factors (for example, cytokines, ROS, and reactive nitrogen species) to result in inhibition of neuronal damage from two triggers of deleterious microglial activation (Aβ and neuron damage), offering hope in halting the progression of AD

Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

Background Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Objective We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Methods Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3) by inhalation over 6 months. Results DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer\u27s disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson\u27s disease-like pathology. Conclusions Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain

Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity

BACKGROUND: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. OBJECTIVES: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. METHODS: Rats were exposed to DE (2.0, 0.5, and 0 mg/m3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. RESULTS: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL-6 (interleukin-6) protein, nitrated proteins, and IBA-1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL-1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. CONCLUSIONS: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity

Looping : an alternative to grade level promotions

This research paper is a study of looping. The purpose of this study was to conduct a review and an analysis of the literature concerning looping. Three questions were asked in the study: 1. What is looping and how does looping differ from multi-age grouping? 2. What are the advantages and disadvantages in looping? 3. What are the guidelines for an effective looping arrangement? The definition of looping was discussed as well as the advantages and disadvantages of looping. Guidelines for an effective looping arrangement were presented. Summary, conclusions, and recommendations were shared with readers

Chlorpyrifos Oxon Primes Microglia: Enhanced LPS-Induced TNFα Production

poster abstractMicroglia, the resident innate immune cells of the brain, respond to various environmental stimuli, including factors from surrounding tissue and from systemic inputs. These stimuli impact microglial function in both health and disease. Increasing evidence implicates microglia and neuroinflammation in Gulf War illness (GWI) pathology. Gulf War illness is an untreatable chronic multi symptomatic disorder that affects about 30% of Gulf War veterans. It has been proposed that “multiple hits” from exposure to various environmental neurotoxicants such as Chlorpyrifos (CPF), an organophosphate pesticide, combined with low inflammation may initiate exaggerated and persistent central nervous system (CNS) pathology to drive GWI. CPF oxon, an active metabolite of CPF, is associated with deleterious CNS effects, but the role of microglia behind this phenomenon is not fully understood.To investigate the effects of CPF oxon on microglia, we assessed microglial ROS, pro-inflammatory cytokine factors, and NF-κB p50 DNA binding activity in the presence of CPF oxon. HAPI microglia cells were treated with CPF oxon (1μM-1nM), which resulted in a dose dependent increase in H2O2 production at 3 hours and elevated superoxide at 30 minutes. CPF oxon failed to initiate TNFα and nitric oxide from microglia cultures. However, CPF oxon significantly decreased NF-κB p50 binding to DNA in microglia, a key redox signaling mechanism linked to microglial priming. Consistent with this premise, pre-treatment with CPF oxon (0.5μM) amplified LPSinduced TNFα production in microglia and neuron-glia cultures. Moreover, when CPF oxon and LPS challenged cells were pre-treated with DPI, a NOX2 inhibitor, we found a significant reduction in TNFα response when compared to non-treated cells, supporting that NOX2 may regulate CPF oxon priming in microglia. These data suggest that CPF oxon may induce ROS production in microglia to reprogram these cells to become more sensitive to pro-inflammatory stimuli (priming)

Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats

Accumulating evidence suggests a deleterious role for urban air pollution in central nervous system (CNS) diseases and neurodevelopmental disorders. Microglia, the resident innate immune cells and sentinels in the brain, are a common source of neuroinflammation and are implicated in how air pollution may exert CNS effects. While renewable energy, such as soy-based biofuel, is of increasing public interest, there is little information on how soy biofuel may affect the brain. To address this, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were exposed to 100% Soy Biodiesel Exhaust (100SBDE; 0, 50, 150 and 500 μg/m3) by inhalation for 4 h/day for 4 weeks (5 days/week). IBA-1 staining of microglia in the substantia nigra revealed significant changes in morphology with 100SBDE exposure in rats from both genotypes, where the SHR were less sensitive. Further analysis failed to show consistent changes in pro-inflammatory cytokine expression, nitrated protein, and arginase1 expression in brain tissue from either rat strain exposed to 100SBDE. CX3CR1 and fractalkine mRNA expression were lower in the striatum of all 100SBDE exposed rats, but greater SBDE exposure was required for loss of fractalkine expression in the SHR. Together, these data support that month-long 100SBDE exposure impacts the basal ganglia with changes in microglia morphology, an impaired fractalkine axis, and an atypical activation response without traditional markers of M1 or M2 activation, where the SHR may be less sensitive to these effects

Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment

Background Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. Methods To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). Results [3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. Conclusions The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-κβ and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site

Occupational Therapy with Australian Indigenous children and their families: A rural and remote perspective

Background/aim: Occupational therapy service delivery must be adapted when working with Indigenous communities, as there is a diversity of beliefs, values and customs. There are currently no evidence-based models of therapy service delivery to rural and remote Indigenous children and their families. This study aims to explore occupational therapy service delivery to rural and remote Indigenous children and their families. Methods: Semi-structured telephone interviews were conducted with seven occupational therapists with experience with Australian rural and remote Indigenous children and their families. A thematic analysis was conducted on each interview with constant comparison to refine themes across interviews. Results: A total of six service delivery themes emerged from the data gathered in the interviews; flexible and accessible services; tailored services; culturally sensitive therapist; culturally inclusive services; occupational therapy awareness; and collaboration. These results linked with the need for long-term solutions, as the limited access to occupational therapy within these communities is a social injustice. Conclusion: The findings demonstrate that each Indigenous community is unique. Therapists work in collaboration with the community and use their critical reasoning skills to adjust practice accordingly. Significance of the study: This study contributes to growing knowledge about occupational therapy service provision in rural and remote Indigenous communities with children and their families. The findings will assist therapist in these communities to provide culturally aligned services. They also advocate for these communities by emphasising the basic human right violations that Indigenous communities are experiencing by not having access to consistent and culturally appropriate occupational therapy services

Le Nuove Musiche

Center for the Performing Arts Tuesday Evening March 18, 2003 8:00p.m