Amyloid-ß (Aß) is best known as the misfolded peptide that is involved in the pathogenesis of Alzheimer's disease (AD), and it is currently the primary therapeutic target in attempts to arrest the ...course of this disease. This notoriety has overshadowed evidence that Aß serves several important physiological functions. Aß is present throughout the lifespan, it has been found in all vertebrates examined thus far, and its molecular sequence shows a high degree of conservation. These features are typical of a factor that contributes significantly to biological fitness, and this suggestion has been supported by evidence of functions that are beneficial for the brain. The putative roles of Aß include protecting the body from infections, repairing leaks in the blood-brain barrier, promoting recovery from injury, and regulating synaptic function. Evidence for these beneficial roles comes from
and
studies, which have shown that the cellular production of Aß rapidly increases in response to a physiological challenge and often diminishes upon recovery. These roles are further supported by the adverse outcomes of clinical trials that have attempted to deplete Aß in order to treat AD. We suggest that anti-Aß therapies will produce fewer adverse effects if the known triggers of Aß deposition (e.g., pathogens, hypertension, and diabetes) are addressed first.
The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not ...slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.
Improvements in the understanding of the metabolic cross-talk between cancer and its microenvironment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have ...increased mitochondria compared with nonmalignant CD34+ hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, AML relies on oxidative phosphorylation to generate adenosine triphosphate. Here we report that in human AML, NOX2 generates superoxide, which stimulates bone marrow stromal cells (BMSC) to AML blast transfer of mitochondria through AML-derived tunneling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis, and improve NSG AML mouse survival. Although mitochondrial transfer from BMSC to nonmalignant CD34+ cells occurs in response to oxidative stress, NOX2 inhibition had no detectable effect on nonmalignant CD34+ cell survival. Taken together, we identify tumor-specific dependence on NOX2-driven mitochondrial transfer as a novel therapeutic strategy in AML.
•Functional mitochondria are transferred in vivo from BMSC to the leukemic blast.•AML-derived NOX2 drives transfer of mitochondria via the generation of superoxide.
Sclerotinia sclerotiorum causes stem rot in Brassica napus, which leads to lodging and severe yield losses. Although recent studies have explored significant progress in the characterization of ...individual S. sclerotiorum pathogenicity factors, a gap exists in profiling gene expression throughout the course of S. sclerotiorum infection on a host plant. In this study, RNA-Seq analysis was performed with focus on the events occurring through the early (1 h) to the middle (48 h) stages of infection.
Transcript analysis revealed the temporal pattern and amplitude of the deployment of genes associated with aspects of pathogenicity or virulence during the course of S. sclerotiorum infection on Brassica napus. These genes were categorized into eight functional groups: hydrolytic enzymes, secondary metabolites, detoxification, signaling, development, secreted effectors, oxalic acid and reactive oxygen species production. The induction patterns of nearly all of these genes agreed with their predicted functions. Principal component analysis delineated gene expression patterns that signified transitions between pathogenic phases, namely host penetration, ramification and necrotic stages, and provided evidence for the occurrence of a brief biotrophic phase soon after host penetration.
The current observations support the notion that S. sclerotiorum deploys an array of factors and complex strategies to facilitate host colonization and mitigate host defenses. This investigation provides a broad overview of the sequential expression of virulence/pathogenicity-associated genes during infection of B. napus by S. sclerotiorum and provides information for further characterization of genes involved in the S. sclerotiorum-host plant interactions.
Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of ...cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment.
•Bone marrow adipocytes support AML survival.•AML induces adipocyte lipolysis of triglyceride to free fatty acids and subsequent transport by FABP4.
Here we provide a protocol for quantitative three-dimensional ex vivo mouse aortic ring angiogenesis assays, in which developing microvessels undergo many key features of angiogenesis over a ...timescale similar to that observed in vivo. The aortic ring assay allows analysis of cellular proliferation, migration, tube formation, microvessel branching, perivascular recruitment and remodeling-all without the need for cellular dissociation-thus providing a more complete picture of angiogenic processes compared with traditional cell-based assays. Our protocol can be applied to aortic rings from embryonic stage E18 through to adulthood and can incorporate genetic manipulation, treatment with growth factors, drugs or siRNA. This robust assay allows assessment of the salient steps in angiogenesis and quantification of the developing microvessels, and it can be used to identify new modulators of angiogenesis. The assay takes 6-14 d to complete, depending on the age of the mice, treatments applied and whether immunostaining is performed.
Obstructive sleep apnea (OSA) is commonly associated with memory impairments. Although MRI studies have found volumetric differences in the hippocampus of people with OSA compared with controls, MRI ...lacks the spatial resolution to detect changes in the specific regions of the hippocampus that process different types of memory. The present study performed histopathological investigations on autopsy brain tissue from 32 people with OSA (17 females and 15 males) to examine whether the thickness and myelination of the hippocampus and entorhinal cortex (EC) vary as a function of OSA severity. Increasing OSA severity was found to be related to cortical thinning in the molecular layer of the dentate gyrus (r2 = 0.136, p = 0.038), the CA1 (overall, r2 = 0.135, p = 0.039; layer 1, r2 = 0.157, p = 0.025; layer 2, r2 = 0.255, p = 0.003; and layer 3, r2 = 0.185, p = 0.014) and in some layers of the EC (layer 1, r2 = 0.186, p = 0.028; trend in layer 3, r2 = 0.124, p = 0.078). OSA severity was also related to decreased myelin in the deep layers but not the superficial layers of the EC (layer 6, r2 = 0.282, p = 0.006; deep white matter, r2 = 0.390, p = 0.001). Patients known to have used continuous positive airway pressure (CPAP) treatment showed no significant reductions in cortical thickness when compared with controls, suggesting that CPAP had a protective effect. However, CPAP did not protect against myelin loss. The regions of decreased cortical thickness and demyelination are locations of synaptic connections in both the polysynaptic (episodic and spatial) and direct (semantic) memory pathways and may underpin the impairments observed in episodic, semantic, and spatial memory in people with OSA.
Abstract
Obstructive sleep apnea (OSA) involves intermittent cessations of breathing during sleep. People with OSA can experience memory deficits and have reduced hippocampal volume; these features ...are also characteristic of Alzheimer’s disease (AD), where they are accompanied by neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques in the hippocampus and brainstem. We have recently shown reduced hippocampal volume to be related to OSA severity, and although OSA may be a risk factor for AD, the hippocampus and brainstems of clinically verified OSA cases have not yet been examined for NFTs and Aβ plaques. The present study used quantitative immunohistochemistry to investigate postmortem hippocampi of 34 people with OSA (18 females, 16 males; mean age 67 years) and brainstems of 24 people with OSA for the presence of NFTs and Aβ plaques. OSA severity was a significant predictor of Aβ plaque burden in the hippocampus after controlling for age, sex, body mass index (BMI), and continuous positive airway pressure (CPAP) use. OSA severity also predicted NFT burden in the hippocampus, but not after controlling for age. Although 71% of brainstems contained NFTs and 21% contained Aβ plaques, their burdens were not correlated with OSA severity. These results indicate that OSA accounts for some of the “cognitively normal” individuals who have been found to have substantial Aβ burdens, and are currently considered to be at a prodromal stage of AD.
Purpose: To determine the chair stand test protocol that is most suitable for older adults in clinical settings by reviewing the currently available methods.
Methods: Five electronic English ...databases were searched and details of methods used on individuals aged ≥65 years in the included studies were compared, including the instrument used to record time, units of measurement, chair characteristics (seat height, armrests), footwear, permission to use upper extremities and walking aids, pace of performance, total number of chair stands, timing points, total number of recorded and practice tests.
Results: A total of 23 eligible studies were identified. The type of instrument to record performance time, characteristics of the chair and footwear were not frequently mentioned. A majority of studies did not permit the use of the upper extremities or walking aids during assessment. The performance of five chair stands at a fast pace recorded in seconds was most common, with the majority of studies recording the initial and end time point in a seated position. The total number of performed tests and practice tests was not specified in a majority of studies.
Conclusion: A feasible and safe protocol for the chair stand test is proposed for assessment of older adults.
Implications for Rehabilitation
The chair stand test may provide valuable information on declines in mobility in older adults.
The use of the chair stand test within clinical settings of older adults may provide a measure to identify frail individuals and to determine their level of frailty.
Using the proposed protocol for the chair stand test may allow for the comparability of results.
Transcranial alternating current stimulation (tACS), a non-invasive and well-tolerated form of electric brain stimulation, can influence perception, memory, as well as motor and cognitive function. ...While the exact underlying neurophysiological mechanisms are unknown, the effects of tACS are mainly attributed to frequency-specific entrainment of endogenous brain oscillations in brain areas close to the stimulation electrodes, and modulation of spike timing dependent plasticity reflected in gamma band oscillatory responses. tACS-related electromagnetic stimulator artifacts, however, impede investigation of these neurophysiological mechanisms. Here we introduce a novel approach combining amplitude-modulated tACS during whole-head magnetoencephalography (MEG) allowing for artifact-free source reconstruction and precise mapping of entrained brain oscillations underneath the stimulator electrodes. Using this approach, we show that reliable reconstruction of neuromagnetic low- and high-frequency oscillations including high gamma band activity in stimulated cortical areas is feasible opening a new window to unveil the mechanisms underlying the effects of stimulation protocols that entrain brain oscillatory activity.
•Reliable, artifact-free MEG source reconstruction during tACS is possible.•Amplitude-modulated tACS entrains brain oscillations.•Entrained brain oscillations can be reliably mapped during tACS.•Opens the door for closed-loop tACS and investing mechanisms of tACS effects
PDF
