Metabotyping of docosahexaenoic acid - Treated alzheimer's disease cell model

10.1371/journal.pone.0090123PLoS ONE92-POLN

Kidney Pathology Precedes and Predicts the Pathological Cascade of Cerebrovascular Lesions in Stroke Prone Rats

INTRODUCTION: Human cerebral small vessel disease (CSVD) has been hypothesized to be an age-dependent disease accompanied by similar vascular changes in other organs. SHRSP feature numerous vascular risk factors and may be a valid model of some aspects of human CSVD. Here we compare renal histopathological changes with the brain pathology of spontaneously hypertensive stroke-prone rats (SHRSP). MATERIAL AND METHODS: We histologically investigated the brains and kidneys of 61 SHRSP at different stages of age (12 to 44 weeks). The brain pathology (aggregated erythrocytes in capillaries and arterioles, microbleeds, microthromboses) and the kidney pathology (aggregated erythrocytes within peritubular capillaries, tubular protein cylinders, glomerulosclerosis) were quantified separately. The prediction of the brain pathology by the kidney pathology was assessed by creating ROC-curves integrating the degree of kidney pathology and age of SHRSP. RESULTS: Both, brain and kidney pathology, show an age-dependency and proceed in definite stages whereas an aggregation of erythrocytes in capillaries and arterioles, we parsimoniously interpreted as stases, represent the initial finding in both organs. Thus, early renal tubulointerstitial damage characterized by rather few intravasal erythrocyte aggregations and tubular protein cylinders predicts the initial step of SHRSPs' cerebral vascular pathology marked by accumulated erythrocytes. The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts. CONCLUSION: Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology. Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage

Mapping the multicausality of Alzheimer's disease through group model building.

Alzheimer's disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD

Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer's Disease Models

Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)sw (Swedish double mutation APP695sw, K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations

Методология синтеза архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки

Предложен подход к проектированию архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки в реальном времени, основанный на классификации решаемых функциональных задач на основе методов кластерного анализа и выбранного множества признаков подобия. Разработанный подход позволяет из множества функций системы выделить подобные (по определенным признакам) и объединить их в архитектурные компоненты (унифицированные функциональные модули).Запропоновано підхід до проектування архітектури центру обробки інформації автоматизованої системи моніторингу середовища в реальному часі, що заснований на класифікації функціональних задач на підставі методів кластерного аналізу і обраної множини ознак схожості. Розроблений підхід дозволяє вибрати із множини функцій системи схожі (за певними ознаками) і поєднати їх в архітектурні компоненти (уніфіковані функціональні модулі).The approach to designing architecture of the information processing complex of the automated real time conditions monitoring system based on classification of functional tasks on the basis of methods of cluster analysis and the chosen set of similarity attributes is offered. The developed approach allows to allocate from a set of functions the systems similar (on certain attributes) and to unite them in architectural components (unified functional modules)

Large-scale unit commitment under uncertainty: an updated literature survey

The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject

A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment

Aims β-amyloid (Aβ) plaques are a key feature of Alzheimer’s disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of Aβ-deposition on the neuropil. This study characterised the astrocyte response to Aβ plaque subtypes, and investigated their association with cognitive impairment. Methods Aβ plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to Aβ and GFAP+ astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): Aβ plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis. Results In the area of densest burden, diffuse plaques with no astrogliosis (β = -0.05, p = 0.001) and with focal astrogliosis (β = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (β = -0.15, p = 0.017 and β = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (β = 0.01, p<0.001 and β = 0.07, p<0.001, respectively), and ApoEε4 genotype (OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoEε4 genotype (OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively). Conclusions Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEε4 allele impacts the astroglial response to Aβ plaques

Fish, docosahexaenoic acid and Alzheimer’s disease

Cognitive decline in the elderly, particularly Alzheimer’s disease (AD), is a major socio-economic and healthcare concern. We review here the literature on one specific aspect of diet affecting AD, that of the ω3 fatty acids, particularly the brain’s principle ω3 fatty acid – docosahexaenoic acid (DHA). DHA has deservedly received wide attention as a nutrient supporting both optimal brain development and for cardiovascular health. Our aim here is to critically assess the quality of the present literature as well as the potential of ω3 fatty acids to treat or delay the onset of AD. We start with a brief description of cognitive decline in the elderly, followed by an overview of well recognized biological functions of DHA. We then turn to epidemiological studies, which are largely supportive of protective effects of fish and DHA against risk of AD. However, biological studies, including blood and brain DHA analyses need careful interpretation and further investigation, without which the success of clinical trials with DHA may continue to struggle. We draw attention to some of the methodological issues that need resolution as well as an emerging mechanism that may explain how DHA could be linked to protecting brain function in the elderly