Search

Alzheimer''s disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidβ (Aβ) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Aβ and the deposition of Aβ in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 months post-lesion. Diffuse amyloid deposits in the deafferented terminal fields of area CA1 and subiculum were dramatically reduced as assessed by image analysis of the Aβ load. Our findings indicate that neuronal ablations decrease diffuse amyloid deposits in the terminal fields of these neurons, and, further, that pathway lesions similarly decrease the amount of diffuse amyloid deposits in the terminal fields of the lesioned axons. Together, this suggests that the axonal transport of APP and/or Aβ and subsequent secretion of Aβ at terminals plays an important role in the deposition of Aβ protein in Alzheimer''s disease, and, further, that diffuse deposits do not develop into plaques.py> [Copyright &y& Elsevier]

We studied the differences between mice and rats in lesion-induced sprouting in the hippocampus. The entorhinal cortex was unilaterally lesioned with ibotenic acid in adult, female mice and rats. Four weeks later the subsequent axonal sprouting in the dentate gyrus was analysed, by measuring the density of the synaptophysin immunohistochemical and acetylcholinesterase histochemical staining in the termination area of the entorhinal cortex axons. The data demonstrate that both mice and rats display a significantly increased density of staining for synaptophysin and acetylcholinesterase in the molecular layer of the dentate gyrus, indicative of axonal sprouting. Both species also show an upregulation in the density of staining for acetylcholinesterase in the molecular layer of the dentate gyrus. Further, rats, but not mice, show a significant upregulation of synaptophysin staining in stratum lacunosum moleculare of CA1 following the lesions. However, whereas rats show significant shrinkage of the molecular layer of the dentate gyrus, mice do not show any shrinkage of that layer following entorhinal cortex lesions. Taken together, these data indicate that whereas the process of reinnervation in the hippocampus is similar between the mouse and the rat, the hippocampal response to denervation shows clear differences between these two species. [Copyright &y& Elsevier]

We describe the case history of a 13-year-old girl with chronic fatigue and prolonged microcytic anaemia. She received oral iron since the age of 11 but failed to respond to it. Laboratory studies revealed elevated C-reactive protein and hypergammaglobulinaemia. A large solitary mesenterial lymph node could be demonstrated by ultrasonography and CT. A diagnosis of Castleman disease was suspected and confirmed histologically. After surgical removal of the lymphoma the patient recovered completely. Conclusion: Castleman disease should be considered in cases of chronic fatigue, unexplained fever, microcytic anaemia and hypergam-maglobulinaemia. [ABSTRACT FROM AUTHOR]

• Loss of PGC-1α in PNs enhances glutamatergic transmission in the neocortex and hippocampus. • Deletion of PGC-1α from pyramidal neurons (PNs) caused ambulatory hyperactivity in response to a novel environment. • Extent of downregulation in metabolic and neuron-specific transcripts regulated by PGC-1α in PNs are regionally distinct. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α's roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease. [ABSTRACT FROM AUTHOR]

Abstract: Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer''s Disease (AD) by influencing Aβ metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Aβ deposition in 8- and 15-month-old APPswe/PS1dE9 mice. In addition we investigated whether changes in rCBV precede changes in Aβ deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Aβ load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Aβ deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Aβ load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology. [Copyright &y& Elsevier]

Abstract: The depletion of neuronal calcium binding proteins deprives neurons of the capacity to buffer high levels of intracellular Ca2+ and this leaves them vulnerable to pathological processes, such as those present in Alzheimer''s disease (AD). The aim of the present study was to investigate the expression of the calcium binding proteins, calbindin-D28K, calretinin and parvalbumin in the dentate gyrus (DG) of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice and their non-Tg littermates, as well as the relation with the deposition of human amyloid β (Aβ). We measured the expression of these three proteins at seven different rostro-caudal levels, and in the molecular, granular and polymorphic layers of the DG. We found that, except in the most caudal part of the DG, there is a substantial loss of calbindin-D28K immunoreactivity in all three layers of the DG in APP/PS1 mice compared with the non-Tg mice. Significant loss of calretinin immunoreactivity is present in most of the polymorphic layer of the DG of APP/PS1 mice compared with the non-Tg mice, as well as in the rostral and intermediate part of the inner molecular layer. Compared with the non-Tg mice parvalbumin immunoreactivity is significantly reduced throughout the whole polymorphic layer as well as in the rostral and intermediate part of the granular layer of DG in APP/PS1 mice. The relatively preservation of calbindin immunoreactivity in the caudal part of molecular and granular layers as well as calretinin immunoreactivity in the caudal part of polymorphic layer of the DG is likely related to the lower Aβ expression in those parts of DG. The present data suggest an involvement of calcium-dependent pathways in the pathogenesis of AD and indicate that there exists a subfield and layer-specific decrease in immunoreactivity which is related to the type of calcium-binding protein in APP/PS1 mice. Moreover, it seems that APP expression affects more the calbindin expression then parvalbumin and calretinin expression in the DG of APP/PS1 Tg mice. [Copyright &y& Elsevier]

Abstract: High dietary cholesterol and low dietary docosahexaenoic acid (DHA) intake are risk factors for Alzheimer’s disease (AD). However, it is unclear how these components influence the course of the disease. We investigated the effects of dietary lipids on β-amyloid deposition and blood circulation in the brains of 18-month-old APP/PS1 mice. Starting at 6 months of age, mice were fed a regular rodent chow, a Typical Western Diet (TWD) containing 1% cholesterol, or a diet with a high (0.5%) level of DHA for 12 months. Relative cerebral blood volume (rCBV) and flow (CBF) were determined with 2H MR spectroscopy and gradient echo contrast enhanced MRI. Deposition of β-amyloid was visualized in fixed brain tissue with immunohistochemistry. The TWD diet increased plaque burden in the dentate gyrus of the hippocampus, but did not significantly reduce rCBV. In contrast, the DHA-enriched diet increased rCBV without changing blood flow indicating a larger circulation in the brain probably due to vasodilatation and decreased the amount of vascular β-amyloid deposition. Together, our results indicate that the long-term intake of dietary lipids can impact both brain circulation and β-amyloid deposition, and support the involvement of hemodynamic changes in the development of AD. [Copyright &y& Elsevier]

Transgenic mice carrying human APPswe and PS1-A264E transgenes (A/P mice) have elevated levels of the highly fibrillogenic amyloid Aβ1-42 (Aβ) and develop amyloid plaques around the age of 9 months. Our aim was to find whether the gradual accumulation of Aβ in these mice can be detected with long-term recording of auditory-evoked potentials. The A/P double-mutant mice had impaired auditory gating and a tendency toward increased latency of the cortical N35 response, but these changes were not age-dependent between 7 and 11 months of age. In a control experiment that included also APP and PS1 single-mutant mice, the A/P double-mutant mice had weaker auditory gating than either APP or PS1 mice. In contrast, increased N35 latency was found in both A/P and APP mice compared with nontransgenic or PS1 mice. The Aβ40 and Aβ42 levels were robustly increased in A/P mice and Aβ40 moderately increased also in APP mice. Plaques were deposited only in A/P mice. We conclude that the impaired auditory gating is associated with the overproduction Aβ42 but does not reflect its amount. In contrast, increased N35 latency is related to the APP genotype independent of Aβ42 production. [Copyright &y& Elsevier]

Recent studies in cell cultures have shown that modulating the cholinergic activity can influence the processing and metabolism of amyloid precursor protein (APP). To investigate whether acetylcholinesterase inhibitors (ChEIs) could decrease production of amyloid β-peptide (Aβ) and slow down the accumulation of Aβ also in vivo, we chronically administered metrifonate (100 mg/kg, po), a second-generation ChEI, to 7-month-old doubly transgenic APP+PS1 mice and their nontransgenic littermate controls for 7 months. Behavioral studies, including open field test, T maze, and water maze, were conducted after 6 months treatment with metrifonate, and the mice were sacrificed at the age of 14 months for biochemical and histological analyses. The long-term treatment with metrifonate failed to inhibit the marked overproduction and deposition of Aβ in the APP+PS1 mice; in contrast, it increased both Aβ40 and Aβ42 levels in the hippocampus. However, the Aβ42 to 40 ratio was significantly reduced by the treatment. In addition, the number of amyloid plaques in the hippocampus did not differ between the treatment and the control groups. Tolerance to cholinesterase inhibition might be induced in the mouse brain because the inhibition rate of AChE was attenuated from about 80 to 50% during the experiment in both APP+PS1 and nontransgenic mice. The metrifonate treatment did not affect cognitive testing parameters but reduced swimming speed and locomotor activity in both genotypes. Our results do not support the idea that ChEIs would slow down the progression of amyloid pathology in Alzheimer''s disease. [Copyright &y& Elsevier]

The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout- Ctsd KO (CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethality on Day 26 ± 1. Overexpression of wildtype CTSD, but not cathepsin B, L or mutant CTSD, decreased α -synuclein toxicity in worms and mammalian cells. In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA. After crossing with Nestin - cre , the STOP cassette is deleted in NESTIN + cells to allow CTSD overexpression- CTSD tg (CDtg). The CDtg mice exhibited normal behavior and similar sensitivity to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration. By breeding CDtg mice with CDKO mice, we found that over-expression of CTSD extended the lifespan of the CDKO mice, partially rescued proteasomal deficits and the accumulation of A β 42 in the CDKO. This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo ., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Interventions for animal lifespan extension like caloric restriction (CR) have identified physiologic and biochemical pathways related to hunger and energy-sensing status as possible contributors, but mechanisms have not been fully elucidated. Prior studies using ghrelin agonists show greater food intake but no effect on lifespan in rodent models. This experiment in male C57BL/6J mice tested the influence of ghrelin agonism for perceived hunger, in the absence of CR, on longevity. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily (12:12 cycle), animals were fed a ghrelin agonist pill (LY444711; Eli Lilly) or a placebo control (Ctrl) until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by Ctrl (ad libitum feeding) the prior week. Results indicate an increased lifespan effect (log-rank p = 0.0032) for GhrAg versus placebo Ctrl, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Nitric oxide (NO) is a gaseous signaling molecule, which plays crucial roles in various biological processes, including inflammatory responses, metabolism, cardiovascular functions, and cognitive function. NO bioavailability is reduced with aging and cardiometabolic disorders in humans and rodents. NO stimulates the metabolic rate by increasing the mitochondrial biogenesis and brown fat activation. Therefore, we propose a novel technology of providing exogenous NO to improve the metabolic rate and cognitive function by promoting the development of brown adipose tissue. In the present study, we demonstrate the effects of the peptide amphiphiles-NO-releasing nanomatrix gel (PANO gel) on high-fat diet-induced obesity, insulin resistance, and cognitive functions. Eight-week-old male C57BL/6 mice were subcutaneously injected in the brown fat area with the PANO gel or vehicle (PA gel) every 2 weeks for 12 weeks. The PANO gel-injected mice gained less body weight, improved glucose tolerance, and decreased fasting serum insulin and leptin levels compared with the PA gel-injected mice. Insulin signaling in the muscle, liver, and epididymal white adipose tissue was improved by the PANO gel injection. The PANO gel reduced inflammation, increased lipolysis in the epididymal white adipose tissue, and decreased serum lipids and liver triglycerides. Interestingly, the PANO gel stimulated uncoupled protein 1 gene expression in the brown and beige fat tissues. Furthermore, the PANO gel increased the cerebral blood flow and improved learning and memory abilities. Our results suggest that using the PANO gel to supply exogenous NO is a novel technology to treat metabolic disorders and cognitive dysfunctions.

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's disease and ulcerative colitis patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease patients remains unknown. Studies have linked the Th17 subset of CD4 + T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis, ischemic brain injury, and Alzheimer's disease. To better understand how CD4 + T lymphocytes contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4 + T cells infiltrate the brain of colitic Rag1 -/- T cells expressed Th17 cell transcription factor retinoic acid-related orphan receptor γt (RORγt) and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4 + T cells failed to cause brain inflammation and neurobehavioral disorders in + T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1 T cells. The finding is mirrored in chronic dextran sulfate sodium-induced colitis in -/- recipients, with significantly less brain infiltration of CD4 + T cells and astrogliosis despite onset of significantly more severe colitis compared with wild-type mice. These findings suggest that pathogenic RORγt Rorc fl/fl Cd4-Cre mice that showed lower frequency of brain-infiltrating CD4 + T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.+ CD4 + T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Synchronous primary malignancies present challenges in diagnosis, treatment sequencing and management. We present a rare case of a synchronous oral cavity and lymphoproliferative malignancy in a middle-age man. Our patient presented with a primary oral cavity squamous cell carcinoma and was subsequently found to have a secondary lymphoproliferative malignancy (chronic lymphocytic leukaemia/small lymphocytic lymphoma). The challenge of staging and sequencing of treatment is discussed. In addition, this case highlights the importance of multidisciplinary consultation, designing a personalised treatment plan that is coincident with the standard of care for each malignancy, and close follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with Alzheimer's disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock) in Tg-SwDI mice with human amyloid-beta precursor protein mutations. Here, we report that Tg-SwDI mice failed to show day/night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer's disease symptoms or delay pathological onset., (Copyright © 2021. Published by Elsevier Inc.)

Background: African trypanosomiasis, which is mainly transmitted by tsetse flies (Glossina spp.), is a threat to public health and a significant hindrance to animal production. Tools that can reduce tsetse densities and interrupt disease transmission exist, but their large-scale deployment is limited by high implementation costs. This is in part limited by the absence of knowledge of breeding sites and dispersal data, and tools that can predict these in the absence of ground-truthing., Methods: In Kenya, tsetse collections were carried out in 261 randomized points within Shimba Hills National Reserve (SHNR) and villages up to 5 km from the reserve boundary between 2017 and 2019. Considering their limited dispersal rate, we used in situ observations of newly emerged flies that had not had a blood meal (teneral) as a proxy for active breeding locations. We fitted commonly used species distribution models linking teneral and non-teneral tsetse presence with satellite-derived vegetation cover type fractions, greenness, temperature, and soil texture and moisture indices separately for the wet and dry season. Model performance was assessed with area under curve (AUC) statistics, while the maximum sum of sensitivity and specificity was used to classify suitable breeding or foraging sites., Results: Glossina pallidipes flies were caught in 47% of the 261 traps, with teneral flies accounting for 37% of these traps. Fitted models were more accurate for the teneral flies (AUC = 0.83) as compared to the non-teneral (AUC = 0.73). The probability of teneral fly occurrence increased with woodland fractions but decreased with cropland fractions. During the wet season, the likelihood of teneral flies occurring decreased as silt content increased. Adult tsetse flies were less likely to be trapped in areas with average land surface temperatures below 24 °C. The models predicted that 63% of the potential tsetse breeding area was within the SHNR, but also indicated potential breeding pockets outside the reserve., Conclusion: Modelling tsetse occurrence data disaggregated by life stages with time series of satellite-derived variables enabled the spatial characterization of potential breeding and foraging sites for G. pallidipes. Our models provide insight into tsetse bionomics and aid in characterising tsetse infestations and thus prioritizing control areas., (© 2021. The Author(s).)

It has been demonstrated that in adulthood rodents show newly born neurons in the subgranular layer (SGL) of the dentate gyrus (DG), and in the subventricular zone (SVZ). The neurons generated in the SVZ migrate through the rostral migratory stream (RMS) to the olfactory bulb. One of the markers of newly generated neurons is doublecortin (DCX). The degu similarly shows significant numbers of DCX-labeled neurons in the SGL, SVZ, and RMS. Further, most of the nuclei of these DCX-expressing neurons are also labeled by proliferating nuclear antigen (PCNA) and Ki67. Finally, whereas in rats and mice DCX-labeled neurons are predominantly present in the SGL and SVZ, with only a few DCX neurons present in piriform cortex, the degu also shows significant numbers of DCX expressing neurons in areas outside of SVZ, DG, and PC. Many areas of neocortex in degu demonstrate DCX-labeled neurons in layer II, and most of these neurons are found in the limbic cortices. The DCX-labeled cells do not stain with NeuN, indicating they are immature neurons., 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 © 2021 van Groen, Kadish, Popović, Caballero Bleda, Baño-Otalora, Rol, Madrid and Popović.)

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological processes, including the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, and neuroinflammation, lead to cognitive impairment at middle and eventually later stages of AD progression. Over the last decade, focused efforts have explored repurposed drug approaches for AD pathophysiological mechanisms. Recently, auranofin, an anti-inflammatory drug, was shown to have therapeutic potential in a number of diseases in addition to rheumatoid arthritis. Surprisingly, no data regarding the effects of auranofin on cognitive deficits in AD mice or the influence of auranofin on Aβ pathology and neuroinflammatory processes are available. In the present study, we used 14-month-old transgenic male APP NL-G-F/NL-G-F mice to assess the effects of subchronic administration of auranofin at low doses (1 and 5 mg/kg, intraperitoneal) on spatial memory, Aβ pathology and the expression of cortical and hippocampal proteins (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule-1 (Iba-1)) and proteins related to synaptic plasticity (glutamic acid decarboxylase 67 (GAD67), homer proteins homologue-1 (Homer-1)). The data demonstrated that auranofin significantly decreased Aβ deposition in the hippocampus and the number of Aβ plaques in the cingulate cortex, but it did not have memory-enhancing effects or induce changes in the expression of the studied proteins. Our current results highlight the importance of considering further pre-clinical research to investigate the possible beneficial effects of auranofin on the other pathological aspects of AD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that regulate cell migration, fusion and viability. Previously, we identified a dysregulated miR-486/DOCK3 signaling cascade in dystrophin-deficient muscle, which resulted in the overexpression of DOCK3; however, little is known about the role of DOCK3 in muscle. Here, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. Utilizing Dock3 global knockout (Dock3 KO) mice, we found that the haploinsufficiency of Dock3 in Duchenne muscular dystrophy mice improved dystrophic muscle pathologies; however, complete loss of Dock3 worsened muscle function. Adult Dock3 KO mice have impaired muscle function and Dock3 KO myoblasts are defective for myogenic differentiation. Transcriptomic analyses of Dock3 KO muscles reveal a decrease in myogenic factors and pathways involved in muscle differentiation. These studies identify DOCK3 as a novel modulator of muscle health and may yield therapeutic targets for treating dystrophic muscle symptoms., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Redox homeostasis regulates key cellular signaling in both physiology and pathology. While perturbations result in shifting the redox homeostasis towards oxidative stress are well documented, the influence of reductive stress (RS) in neurodegenerative diseases and its mechanisms are unknown. Here, we postulate that a redox shift towards the reductive arm (through the activation of Nrf2 signaling) will damage neurons and impair neurogenesis. In proliferating and differentiating neuroblastoma (Neuro 2a/N2a) cells, sulforaphane-mediated Nrf2 activation resulted in increased transcription/translation of antioxidants and glutathione (GSH) production along with significantly declined ROS in a dose-dependent manner leading to a reductive-redox state (i.e. RS). Interestingly, this resulted in endoplasmic reticulum (ER) stress leading to subsequent protein aggregation/proteotoxicity in neuroblastoma cells. Under RS, we also observed elevated Tau/α-synuclein and their co-localization with other protein aggregates in these cells. Surprisingly, we noticed that acute RS impaired neurogenesis as evidenced from reduced neurite outgrowth/length. Furthermore, maintaining the cells in a sustained RS condition (for five consecutive generations) dramatically reduced their differentiation and prevented the formation of axons (p < 0.05). This impairment in RS mediated neurogenesis occurs through the alteration of Tau dynamics i.e. RS activates the pathogenic GSK3β/Tau cascade thereby promoting the phosphorylation of Tau leading to proteotoxicity. Of note, intermittent withdrawal of sulforaphane from these cells suppressed the proteotoxic insult and re-activated the differentiation process. Overall, this results suggest that either acute or chronic RS could hamper neurogenesis through GSK3β/TAU signaling and proteotoxicity. Therefore, investigations identifying novel redox mechanisms impacting proteostasis are crucial to preserve neuronal health., (Copyright © 2020. Published by Elsevier B.V.)

PDE4 cyclic nucleotide phosphodiesterases reduce 3', 5' cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β 2 -adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.

Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that is caused by the loss of functional dystrophin protein in cardiac and skeletal muscles. DMD patient muscles become weakened, leading to eventual myofiber breakdown and replacement with fibrotic and adipose tissues. Inflammation drives the pathogenic processes through releasing inflammatory cytokines and other factors that promote skeletal muscle degeneration and contributing to the loss of motor function. Selective inhibitors of nuclear export (SINEs) are a class of compounds that function by inhibiting the nuclear export protein exportin 1 (XPO1). The XPO1 protein is an important regulator of key inflammatory and neurological factors that drive inflammation and neurotoxicity in various neurological and neuromuscular diseases. Here, we demonstrate that SINE compound KPT-350 can ameliorate dystrophic-associated pathologies in the muscles of DMD models of zebrafish and mice. Thus, SINE compounds are a promising novel strategy for blocking dystrophic symptoms and could be used in combinatorial treatments for DMD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O 3 ) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O 3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O 3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O 3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O 3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O 3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development., (Published by Elsevier Inc.)

Purpose: Although the minor salivary gland biopsy (MSGB) is a major criterion for the diagnosis of Sjögren syndrome (SS), multiple studies have outlined difficulties in standardization. The purpose of this study was to answer the following question: in all patients referred for MSGB, did strict application of focus scoring criteria alter the sensitivity of and predictive value of the MSGB in the diagnosis of SS compared with the initial interpretation?, Materials and Methods: The authors designed a cross-sectional study of patients referred to the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery (Boston, MA) over a 5-year period for MSGB. The primary predictor variable was the MSGB focus score. The primary outcome variable was the SS diagnosis. The newly established SS diagnosis status results were compared with the initial SS diagnoses. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated. Other relevant variables of interest, such as size of glandular tissue harvested and associated signs and symptoms, also were documented. The primary predictor variable was the MSGB focus score and the primary outcome variable was the SS diagnosis (positive or negative)., Results: Seventy-three patients met the inclusion criteria. The mean age was 48.5 years (range, 19 to 71 yr) and 64 were women (87.6%). The authors' previous study using initial pathology reports yielded 80.0% sensitivity, 87.5% specificity, 57.1% PPV, and 95.5% NPV. The present review of the MSGB using strict focus scoring guidelines yielded 95.4% sensitivity, 76.4% specificity, 63.6% PPV, and 97.5% NPV., Conclusions: The MSGB is an important major criterion in establishing a diagnosis of SS. Application of strict focus scoring guidelines when reviewing the MSGB yielded a sensitivity far greater than initially reported in this group. Difficulties with interpretation are discussed. Future studies will focus on improvement of interpretation and immunohistochemical aids in diagnosis., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Disruption of circadian rhythms is commonly reported in individuals with Alzheimer's disease (AD). Neurons in the primary circadian pacemaker, the suprachiasmatic nucleus (SCN), exhibit daily rhythms in spontaneous neuronal activity which are important for maintaining circadian behavioral rhythms. Disruption of SCN neuronal activity has been reported in animal models of other neurodegenerative disorders; however, the effect of AD on SCN neurophysiology remains unknown. In this study we examined circadian behavioral and electrophysiological changes in a mouse model of AD, using male mice from the Tg-SwDI line which expresses human amyloid precursor protein with the familial Swedish (K670N/M671L), Dutch (E693Q), Iowa (D694N) mutations. The free-running period of wheel-running behavior was significantly shorter in Tg-SwDI mice compared to wild-type (WT) controls at all ages examined (3, 6, and 10 months). At the SCN level, the day/night difference in spike rate was significantly dampened in 6-8 month-old Tg-SwDI mice, with decreased AP firing during the day and an increase in neuronal activity at night. The dampening of SCN excitability rhythms in Tg-SwDI mice was not associated with changes in input resistance, resting membrane potential, or action potential afterhyperpolarization amplitude; however, SCN neurons from Tg-SwDI mice had significantly reduced A-type potassium current (I A ) during the day compared to WT cells. Taken together, these results provide the first evidence of SCN neurophysiological disruption in a mouse model of AD, and highlight I A as a potential target for AD treatment strategies in the future., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pressure can shift the polymer-monomer equilibrium of Aβ, increasing pressure first leads to a release of Aβ-monomers, surprisingly at pressures higher than 180 MPa repolymerization is induced. By high pressure NMR spectroscopy, differences of partial molar volumes ΔV0 and compressibility factors Δβ' of polymerization were determined at different temperatures. The d-enantiomeric peptides RD2 and RD2D3 bind to monomeric Aβ with affinities substantially higher than those determined for fibril formation. By reducing the Aβ concentration below the critical concentration for polymerization they inhibit the formation of toxic oligomers. Chemical shift perturbation allows the identification of the binding sites. The d-peptides are candidates for drugs preventing Alzheimer's disease. We show that RD2D3 has a positive effect on the cognitive behaviour of transgenic (APPSwDI) mice prone to Alzheimer's disease. The heterodimer complexes have a smaller Stokes radius than Aβ alone indicating the recognition of a more compact conformation of Aβ identified by high pressure NMR before.

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Background: PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored., Results: To specifically disrupt PDE4B1, we developed mice that express a PDE4B1-D564A transgene in the hippocampus and forebrain. The transgenic mice showed enhanced phosphorylation of CREB and ERK1/2 in hippocampus. Hippocampal neurogenesis was increased in the transgenic mice. Hippocampal electrophysiological studies showed increased baseline synaptic transmission and enhanced LTP in male transgenic mice. Behaviorally, male transgenic mice showed increased activity in prolonged open field testing, but neither male nor female transgenic mice showed detectable anxiety-like behavior or antidepressant effects in the elevated plus-maze, tail-suspension or forced-swim tests. Neither sex showed any significant differences in associative fear conditioning or showed any demonstrable abnormalities in pre-pulse inhibition., Conclusions: These data support the use of an isoform-selective approach to the study of PDE4B1 function in the CNS and suggest a probable role of PDE4B1 in synaptic plasticity and behavior. They also provide additional rationale and a refined approach to the development of small-molecule PDE4B1-selective inhibitors, which have potential functions in disorders of cognition, memory, mood and affect.

Purpose: Sjögren syndrome (SS), although commonly associated with xerostomia and xerophthalmia, can present with extraglandular manifestations that make definitive diagnosis difficult. The 2 leading diagnostic classification systems include a positive minor salivary gland biopsy (MSGB) result as a major inclusion criterion. The purpose of this study was to better define the role of the MSGB in establishing a diagnosis of SS in a cohort of referred patients., Materials and Methods: This is a retrospective cohort study of patients referred to the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery (Boston, MA) over a 5-year period to establish a diagnosis of SS. Inclusion criteria were complete information regarding presenting symptoms, reason for referral, and findings at MSGB. Incomplete records and referral for reasons other than presumptive SS resulted in exclusion. The MSGB and its role in definitive diagnosis based on accepted classification systems were evaluated for sensitivity, specificity, and positive and negative predictive values. Other variables of interest (demographics, pattern of referral, and symptomology) are described for the cohort., Results: Eighty-seven patients met the inclusion criteria. The mean age was 48.3 years (range, 19 to 74 yr) and 75 were women (86.2%). Fifteen MSGB results (17.2%) were positive based on the focus score histologic criteria. In 12 of 15 cases, the positive MSGB result allowed for a definitive diagnosis (80%). In 3 cases, other criteria allowed diagnosis without the contribution of the MSGB (sensitivity of MSGB, 80.0%; specificity, 87.5%; positive predictive value, 57.1%; negative predictive value, 95.5%)., Conclusion: The MSGB is an important contributor to a diagnosis of SS. When serology was negative, the MSGB often was the criterion that allowed the diagnosis to be established. It is the most frequently positive of the major criteria used by the 2 classification systems in current use., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

While amyloid-β protein (Aβ) aggregation into insoluble plaques is one of the pathological hallmarks of Alzheimer's disease (AD), soluble oligomeric Aβ has been hypothesized to be responsible for synapse damage, neurodegeneration, learning, and memory deficits in AD. Here, we investigate the in vitro and in vivo efficacy of the D-enantiomeric peptide RD2, a rationally designed derivative of the previously described lead compound D3, which has been developed to efficiently eliminate toxic Aβ42 oligomers as a promising treatment strategy for AD. Besides the detailed in vitro characterization of RD2, we also report the results of a treatment study of APP/PS1 mice with RD2. After 28 days of treatment we observed enhancement of cognition and learning behaviour. Analysis on brain plaque load did not reveal significant changes, but a significant reduction of insoluble Aβ42. Our findings demonstrate that RD2 was significantly more efficient in Aβ oligomer elimination in vitro compared to D3. Enhanced cognition without reduction of plaque pathology in parallel suggests that synaptic malfunction due to Aβ oligomers rather than plaque pathology is decisive for disease development and progression. Thus, Aβ oligomer elimination by RD2 treatment may be also beneficial for AD patients.

Amyloid-beta (Aβ) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Aβ oligomer eliminating d-enantiomeric peptide D3, we developed and applied a two-step procedure based on peptide microarrays to identify D3 derivatives with increased binding affinity and specificity for monomeric Aβ(1-42) to further enhance the Aβ oligomer elimination efficacy. Out of more than 1000 D3 derivatives, we selected seven novel d-peptides, named ANK1 to ANK7, and characterized them in more detail in vitro. All ANK peptides bound to monomeric Aβ(1-42), eliminated Aβ(1-42) oligomers, inhibited Aβ(1-42) fibril formation, and reduced Aβ(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Aβ(1-42) seeds and showed a nonsignificant tendency for improving memory performance of tg-APPSwDI mice after i.p. application for 4 weeks. This supports the hypothesis that stabilization of Aβ monomers and thereby induced elimination of Aβ oligomers is a suitable therapeutic strategy.

OBJECTIVE 17α-ethynylestradiol-3-sulfate (EE-3-SO 4 ) is a highly water-soluble synthetic estrogen that has an extended half-life (∼ 10 hours) over that of naturally occurring estrogen (∼ 10 minutes). In this study, EE-3-SO 4 was evaluated in a lateral fluid percussion-induced traumatic brain injury (TBI) model in rats. METHODS A total of 9 groups of Sprague-Dawley rats underwent craniectomy. Twenty-four hours later, lateral fluid percussion was applied to 6 groups of animals to induce TBI; the remaining 3 groups served as sham control groups. EE-3-SO 4 (1 mg/kg body weight in 0.4 ml/kg body weight) or saline (vehicle control) was injected intravenously 1 hour after TBI; saline was injected in all sham animals. One day after EE-3-SO 4 /saline injection, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (PbtO 2 ) were measured in Groups 1-3 (2 TBI groups and 1 sham group), and brain edema, diffusion axonal injury, and cerebral glycolysis were assessed in Groups 4-6 using MRI T2 mapping, diffusion tensor imaging (DTI), and FDG-PET imaging, respectively. Four days after dosing, the open-field anxiety of animals was assessed in Groups 7-9 by measuring the duration that each animal spent in the center area of an open chamber during 4 minutes of monitoring. RESULTS EE-3-SO 4 significantly lowered ICP while raising CPP and PbtO 2 , compared with vehicle treatment in TBI-induced animals (p < 0.05). The mean size of cerebral edema of TBI animals treated with EE-3-SO 4 was 25 ± 3 mm 3 (mean ± SE), which was significantly smaller than that of vehicle-treated animals (67 ± 6 mm 3 , p < 0.001). Also, EE-3-SO 4 treatment significantly increased the fractional anisotropy of the white matter in the ipsilateral side (p = 0.003) and cerebral glycolysis (p = 0.014). The mean duration that EE-3-SO 4 -treated animals spent in the center area was 12 ± 2 seconds, which was significantly longer than that of vehicle-treated animals (4 ± 1 seconds; p = 0.008) but not different from that of sham animals (11 ± 3 seconds; p > 0.05). CONCLUSIONS These data support the clinical use of EE-3-SO 4 for early TBI treatment.