Inflammation as a central mechanism in Alzheimer's disease Kinney, Jefferson W.; Bemiller, Shane M.; Murtishaw, Andrew S. ...
Alzheimer's & dementia : translational research & clinical interventions,
2018, Letnik:
4, Številka:
1
Journal Article
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary ...tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
The gut microbiome is a critical modulator of systemic physiology, including infectious disease susceptibility. Although this niche is a reservoir for uropathogenic Escherichia coli, knowledge of its ...role in urinary tract infections (UTIs) is limited. We discuss two recent studies, Thänert et al. (2022) and Worby et al. (2022), that interrogate the roles of the gut-bladder axis in UTIs.
The gut microbiome is a critical modulator of systemic physiology, including infectious disease susceptibility. Although this niche is a reservoir for uropathogenic Escherichia coli, knowledge of its role in urinary tract infections (UTIs) is limited. We discuss two recent studies, Thänert et al. (2022) and Worby et al. (2022), that interrogate the roles of the gut-bladder axis in UTIs.
Dietary berries, such as strawberries, are rich in bioactive compounds and have been shown to lower cardiometabolic risk. We examined the effects of two dietary achievable doses of strawberries on ...glycemic control and lipid profiles in obese adults with elevated serum LDL cholesterol (LDL-C).
In this 14-week randomized controlled crossover study, participants were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or two-and-a -half servings (high dose: 32 g strawberry powder/day). Participants were instructed to follow their usual diet and lifestyle while refraining from consuming other berries and related products throughout the study interval. Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention.
In total, 33 participants completed all three phases of the trial (mean ± SD): Age: 53 ± 13 y; BMI: 33 ± 3.0 kg/m
). Findings revealed significant reductions in fasting insulin (
= 0.0002) and homeostatic model of assessment of insulin resistance (
= 0.0003) following the high dose strawberry phase when compared to the low dose strawberry and control phases. Glucose and conventional lipid profiles did not differ among the phases. Nuclear magnetic resonance-determined particle concentrations of total VLDL and chylomicrons, small VLDL, and total and small LDL were significantly decreased after the high dose strawberry phase, compared to control and low dose phases (all
< 0.0001). Among the biomarkers of inflammation and adipokines measured, only serum PAI-1 showed a decrease after the high dose strawberry phase (
= 0.002).
These data suggest that consuming strawberries at two-and-a-half servings for four weeks significantly improves insulin resistance, lipid particle profiles, and serum PAI-1 in obese adults with elevated serum LDL-C.
A global increase in older individuals creates an increasing demand to understand numerous healthcare challenges related to aging. This population is subject to changes in tissue physiology and the ...immune response network. Older individuals are particularly susceptible to infectious diseases, with one of the most common being urinary tract infections (UTIs). Postmenopausal and older women have the highest risk of recurrent UTIs (rUTIs); however, why rUTIs become more frequent after menopause and during old age is incompletely understood. This increased susceptibility and severity among older individuals may involve functional changes to the immune system with age. Aging also has substantial effects on the epithelium and the immune system that led to impaired protection against pathogens, yet heightened and prolonged inflammation. How the immune system and its responses to infection changes within the bladder mucosa during aging has largely remained poorly understood. In this review, we highlight our understanding of bladder innate and adaptive immunity and the impact of aging and hormones and hormone therapy on bladder epithelial homeostasis and immunity. In particular, we elaborate on how the cellular and molecular immune landscape within the bladder can be altered during aging as aged mice develop bladder tertiary lymphoid tissues (bTLT), which are absent in young mice leading to profound age-associated change to the immune landscape in bladders that might drive the significant increase in UTI susceptibility. Knowledge of host factors that prevent or promote infection can lead to targeted treatment and prevention regimens. This review also identifies unique host factors to consider in the older, female host for improving rUTI treatment and prevention by dissecting the age-associated alteration of the bladder mucosal immune system.
•Aging is associated with increased susceptibility to rUTIs.•Aged mice develop bladder tertiary lymphoid tissues (bTLT).•bTLT are associated with significant increase in UTI frequency in mice and women.•Urothelial permeability and urobiome species change with age and menopausal status.•Multimodal therapies can lead to bTLT regression and improved rUTI outcomes.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive decline of memory and cognitive function. The disease is characterized by the presence of amyloid plaques, ...tau tangles, altered inflammatory signaling, and alterations in numerous neurotransmitter signaling systems, including γ-aminobutyric acid (GABA). Given the extensive role of GABA in regulating neuronal activity, a careful investigation of GABA-related changes is needed. Further, given persistent inflammation has been demonstrated to drive AD pathology, the presence of GABA B receptor expressed on glia that serve a role regulation of the immune response adds to potential implications of altered GABA in AD. There has not previously been a systematic evaluation of GABA-related changes in an amyloid model of AD that specifically focuses on examining changes in GABA B receptors. In the present study, we examined alterations in several GABA-specific targets in the APP/PS1 mouse model at different ages. In the 4-month-old cohort, no significant deficits in spatial learning and memory or alterations in any of the GABAergic targets were observed compared with wild-type controls. However, we identified significant alterations in several GABA-related targets in the 6-month-old cohort that exhibited spatial learning deficits that include changes in glutamic acid decarboxylase 65, GABA transporter type 3, and GABA B receptors protein and mRNA levels. This was the same cohort at which learning and memory deficits and significant amyloid pathology was observed. Overall, our study provides evidence of altered GABAergic signaling in an amyloid model of AD at a time point consistent with AD-related deficits.
•Amyloid pathology in the APP/PS1 mouse models results in changes in proteins associated with GABA synthesis and transport (GAD-65 and GAT3).•APP/PS1 mice exhibit reductions in total protein and mRNA for all 3 subunits of the GABAB receptor in the hippocampus.•Given the data indicating significant changes in GABAB due to amyloid pathology and that GABAB is expressed on neurons and glia the findings in the present study represent a novel mechanism altered in Alzheimer's disease that impacts neuronal and glial function.
Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. ...Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1β-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.
Pregnancies affected by obesity are at high risk for developing metabolic complications with oxidative stress and adipocyte dysfunction contributing to the underlying pathologies. Few studies have ...examined the role of dietary interventions, especially those involving antioxidants including polyphenolic flavonoids found in fruits and vegetables on these pathologies in high-risk pregnant women. We conducted an 18 gestation-week randomized controlled trial to examine the effects of a dietary intervention comprising of whole blueberries and soluble fiber vs. control (standard prenatal care) on biomarkers of oxidative stress/antioxidant status and adipocyte and hormonal functions in pregnant women with obesity (
= 34). Serum samples were collected at baseline (<20 gestation weeks) and at the end of the study period (32-26 gestation weeks). Study findings showed maternal serum glutathione and antioxidant capacity to be significantly increased, and malondialdehyde to be decreased in the dietary intervention vs. control group (all
< 0.05). Among the adipokine biomarkers, serum plasminogen activator inhibitor-1 and visfatin, as biomarkers of adipocyte dysfunction and insulin resistance, were also decreased following dietary intervention (all
< 0.05). These findings support the need for supplementing maternal diets with berries and fiber to improve oxidative stress and risks of metabolic complications during pregnancy.
Este trabajo tiene como objetivo diseñar un control de corriente por realimentación de estados, basado en desigualdades matriciales lineales (LMI) aplicado en un convertidor modular DC-DC Buck-Boost ...de inductores acoplados, el cual ha sido ampliamente utilizado en sistemas de generación distribuida con fuentes de energías renovables. Este método considera restricciones en la ubicación de polos definidas en el plano complejo denominadas d-stability. El sistema de control en lazo cerrado se implementa en Simulink de Matlab® y se valida ante diferentes escenarios de prueba, donde se obtienen mejores prestaciones dinámicas, se amplía su rango de operación, con tiempos de establecimiento menores y una mejor respuesta temporal, en contraste con la técnica de control PI clásica.
Pollen germination represents the transition from mature to germinated pollen, which is a critical event in seed plant reproduction. Cell wall–related processes represent many of the cellular ...activities during this transition but information on the genes involved is limited, particularly in gymnosperms. Yeast secretion trap (YST) is employed in the current study to isolate cDNAs encoding secretory proteins associated with in vitro germinated pollen of loblolly pine (
Pinus taeda
). YST is a functional screen and when coupled with computational prediction provides insights on the diversity of populations, subcellular localizations, and functions of the encoded proteins. Based on 100 confirmed YST clones, our results identified 21 known, 4 unknown, and 10 hypothetical genes encoding secretory proteins, which are mostly predicted to be localized in the plasma membrane or extracellular space. Based on the known sequences, pollen germination involves genes associated with cell wall degradation, biosynthesis and remodeling, stress and defense responses, signaling, and protein processing. This study characterizes further 10 highly expressed cDNAs based on their temporal (mature pollen vs germinated pollen) and spatial (germinated pollen, young stem, and needle tissue) expression patterns, as well as sequence features such as the presence of transmembrane α-helix, glycosylphosphatidylinositol anchor, and conserved domains. It appears that pine pollen germination involves genes with static and dynamic expression profiles including those with germination-specific expressions. This study confirms the distinct expression profiles of mature and germinated pollen, and expands our understanding of the likely molecular players and processes associated with pine pollen germination, particularly pollen tube wall formation.
Studies suggest that exercise may be neuroprotective when implemented before the clinical presentation of Parkinson's disease (PD). Levels of brain-derived neurotrophic factor (BDNF), theorized to ...play a role in neuroprotection, are affected by its genotype and exercise. Here we explore this previously unstudied interaction on age at diagnosis and severity of symptoms.
76 participants with PD submitted buccal cells to determine BDNF genotype, completed the modified Lifetime Physical Activity Questionnaire to determine exercise habits, and were assessed using the Movement Disorder Society – Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III) and the Mini-Balance Evaluations Test (MBT). For aim 1 (age at diagnosis), 60 participants (age = 69.6 ± 7.4; males = 45, females = 15) were analyzed. For aim 2 (severity of symptoms), 54 participants (age = 70.0 ± 7.6; males = 41, females = 13) were analyzed.
The final hierarchical regression model for age at diagnosis produced an R2 = 0.146, p = .033; however, the only significant variable in the final model was average moderate physical activity from ages 20s to 40s (p = .009). The regression for MDS-UPDRS III was not significant; however, the regression for MBT was, p = .0499. In the final model, 23.1% of the variance was explained. Years since diagnosis (p = .014) and average vigorous physical activity from ages 20s to 40s (p = .047) were the only predictors in the final model.
While a strong interaction between BDNF genotype and lifetime physical activity was not observed, our results suggest that lifetime exercise may be neuroprotective in PD. Specifically, higher amounts of moderate PA were associated with an older age at diagnosis.
•This is the first study to show that pre-diagnosis exercise is associated with age at diagnosis.•Higher amounts of moderate physical activity were associated with an older age at diagnosis.•Every hour increase in weekly moderate physical activity from ages 20–40 was associated with a PD diagnosis 3 months later.
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