Neuroprotective effects of the Alzheimer's disease-related gene seladin-1

The endocrine and the nervous system are closely correlated throughout life, starting from the embryo and until the late stages of life. Alzheimer's disease (AD) is the most common neurodegenerative disease associated with ageing. Unfortunately, an effective way to prevent or to cure this disease does not exist, so far. There is evidence that estrogens exert neuroprotective properties, although their efficacy against AD is still a matter of debate. In 2000 a new neuroprotective gene, i.e. seladin-1 (for SELective AD INdicator-1) was identified and found to be down regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. This protein has also enzymatic activity. In fact, it has been demonstrated that the seladin-1 gene encodes 3-beta-hydroxysterol Delta-24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. In recent years, it has been demonstrated that an appropriate amount of membrane cholesterol determines the generation of a barrier against toxic insults and prevents the production of beta-amyloid, the histopathological hallmark of AD. This review will summarize the studies that have been focused on the characterization of the biological properties of seladin-1 since its first identification. In particular, the relationship between seladin-1-mediated neuroprotection and estrogens, IGF1 and thyroid hormones, will be described and discussed.     

Visual recognition memory in Alzheimer's disease: repetition-lag effects

There is considerable evidence that visual recognition memory is largely affected by Alzheimer's disease (AD). Deficits might concern the forming, maintaining, and matching of the memory representation of the visual stimulus, especially when long interitem lags occur. The aim of the present study was to assess the effect of repetition lag on picture identification in mild- and moderate-AD patients, as well as in elderly controls. Participants underwent an old/new paradigm. To manipulate the temporal gradient, short and long lags were introduced between the first and second presentations. Pictures were presented at different levels of spatial filtering, following a coarse-to-fine order. This allowed for the measurement of the amount of physical information required for the identification of stimuli as a function of prior exposure and repetition lag. In the elderly, the magnitude of repetition priming did not differ as a function of interitem lag. Instead, repetition-lag effects interacted with dementia severity, and the capacity to retain memory traces for longer intervals worsened as the disease progresses. Current findings suggest that severe cortical degeneration may render AD patients unable to maintain their perceptual memories, and that dementia severity is a critical variable in the visual recognition memory assessment.     

Anti-obesity and anti-diabetic effects of brain-derived neurotrophic factor in rodent models of leptin resistance

OBJECTIVE: Obesity in rodents and humans is mostly associated with elevated plasma leptin concentrations, suggesting a new pathological concept of 'leptin resistance'. We have demonstrated that brain-derived neurotrophic factor (BDNF) can improve obesity and diabetes of C57BL/KsJ db/db (db/db) mice. In this study, we investigated whether or not BDNF is effective in two different models of leptin resistance, an acquired model and a genetic model. DESIGN: C57BL/6J mice rendered obese by consumption of a high-fat diet (diet-induced obesity (DIO) mice) were used as an acquired model and lethal yellow agouti mice (KKA(y) mice) as a genetic model of leptin resistance. Food intake and glucose metabolism were studied after acute or repetitive administration of BDNF. RESULTS: Intraperitoneal administration of BDNF (10 mg/kg, twice/day) significantly reduced cumulative food intake of DIO and KKA(y) mice, whereas they were unresponsive to leptin administration. Repetitive subcutaneous administration of BDNF (10 mg/kg daily for 6 days) reduced food intake and improved impaired glucose tolerance in DIO mice. Pair feeding of vehicle-treated DIO mice with the same amount of chow consumed by the BDNF-treated group did not improve the impaired glucose homeostasis, indicating that the antidiabetic effect is not due to decreased food intake. We also observed that BDNF is effective in improving obesity and diabetes of KKA(y) mice. CONCLUSION: This study demonstrated antiobesity and antidiabetic effects of BDNF in two different models of leptin resistance, thereby suggesting the therapeutic potential of BDNF in the treatment of leptin-resistant obesity and diabetes.     

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer''s disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer''s mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Aβ) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.     

Inheritance of ventilatory behavior in rodent models

Studies in mice and rats support the hypothesis that ventilation and its components (frequency and tidal volume) are determined to a significant extent by genetic mechanisms. The question can no longer be 'is there a genetic effect?' but rather 'how strong is the genetic component?' and 'what genes are involved?' The computational analyses of selectively bred animals now offer powerful tools to begin to dissect the genetic factors that track with ventilatory traits. Control of the conditions in the colony and in the laboratory are keys to reducing the environmental 'noise' and increasing the likelihood of detecting gene loci that correlate quantitatively with phenotype values before and during the response to chemosensory challenges. Knowing the chromosomal location of genes for ventilation will then permit the identification of proteins systems responsible for the structural and functional components for respiration.     

卒中后早期运动训练的神经保护作用

卒中后早期运动训练的治疗策略已是一个备受关注的热点。一系列研究显示,卒中后早期运动训练能通过抑制急性神经炎性反应和细胞凋亡、增加神经营养因子表达和保护血脑屏障完整性来减轻脑损伤。文章就早期运动训练在卒中后的神经保护作用以及其可能的分子机制进行了综述。     

Bromocriptine reduces steatosis in obese rodent models

BACKGROUND/AIMS: Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. METHODS: We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. RESULTS: Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. CONCLUSIONS: Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.     

米诺环素对缺血性卒中的神经保护作用

米诺环素为第2代半合成四环素类抗生素,多种动物实验模型和临床试验表明其具有神经保护作用,其机制与抑制凋亡、减轻炎性反应、缩小梗死体积和减轻血管损伤有关.文章对急性缺血性卒中临床前期和早期临床试验中米诺环素的神经保护作用进行了综述.     

Prospective memory intervention in Alzheimer's disease.

Four individuals with Alzheimer's disease were trained to remember and to implement an intention for future action. The training program utilized the spaced-retrieval method, which involves active attempts to recall information over expanding intervals of time. All participants learned to select a colored coupon from an array of distractors and offer it to the experimenter after a week's delay. Following one-week retention of the initial task, a different coupon became the new training target. All participants were able to shift to this new task requirement, and all learned three successive coupon colors successfully. These results indicate that individuals with Alzheimer's disease can learn a prospective memory task using spaced-retrieval practice and can make adjustments for changing task requirements.     

Genetic variability and rodent models of human aging.

Inbred strains, outbred strains, and natural populations of rodents differ greatly in the amount and nature of the genetic variability they possess. Consequently, as models of human aging they vary with respect to the areas of research to which they are best suited. Inbred strains, in which all individuals are genetically identical, are best suited as models of specific disease processes and for manipulations involving tissue transplantation. Their lack of genetic variability, however, and the disruption of genetic linkage groups that occurs during inbreeding limit their value as models of more general aging processes. Outbred strains exhibit large interindividual genetic variation--a result of ongoing random accumulation of deleterious alleles with late ages of action. This makes them ideal models for studying the diversity of pathologic lesions, connections between pathologies, and susceptibility to pathologic lesions that collectively produce the reductions in reproductive capacity, physiological efficiency, and viability that are characteristic of aging. Natural populations also may exhibit relatively large amounts of interindividual genetic variability. However, difficulties with husbandry, variable parasite loads, and complex population genetics can compromise their suitability as models of human aging. Ultimately, a consideration of the range of animal models available and a more careful matching of the goals of a study with the genetic system of the model will prove fruitful to gerontology.     

Neuroprotective effects of estradiol in middle-aged female rats

Estrogen replacement therapy in postmenopausal women ameliorates cognitive dysfunction and decreases the risk and/or severity of neurodegenerative conditions such as Alzheimer's disease and stroke. Furthermore, estradiol exerts neuroprotective effects in a variety of in vitro and in vivo models of brain injury. We have previously shown that physiological levels of estradiol attenuate ischemic brain injury in young female rats. However, neurodegenerative events occur more frequently in elderly women who are chronically hypoestrogenic. Therefore, we investigated whether aging rats remain responsive to the neuroprotective actions of estradiol. Young (3-4 months) and middle-aged (9-12 months) rats were ovariectomized and treated for 1 week with estradiol before middle cerebral artery occlusion (MCAO). Regional cerebral blood flow was monitored in some animals at the time of injury. Brains were collected 24 h after MCAO and infarct volume was analyzed. Our data demonstrate that in both young and aging rats, low and high physiological doses of estradiol decrease ischemic injury by almost 50%, compared with oil-treated controls. Additionally, our data suggest that estradiol acts in both age groups via blood flow-independent mechanisms, as basal and postinjury blood flow was equivalent between estradiol- and oil-treated young and aging rats. These data demonstrate that replacement with physiological levels of estradiol protects against stroke-related injury in young and aging female rats and strongly suggest that older animals remain responsive to the protective actions of estradiol.     

The role of working memory and attentional disengagement on inhibitory control: effects of aging and Alzheimer's disease

Patients with Alzheimer''s disease have an impairment of inhibitory control for reasons that are currently unclear. Using an eye-tracking task (the gap-overlap paradigm), we examined whether the uncorrected errors relate to the task of attentional disengagement in preparation for action. Alternatively, the difficulty in correcting for errors may be caused by the working memory representation of the task. A major aim of this study was to distinguish between the effects of healthy aging and neurodegenerative disease on the voluntary control of saccadic eye movements. Using the antisaccade task (AST) and pro-saccade task (PST) with the ‘gap’ and ‘overlap’ procedures, we obtained detailed eye-tracking measures in patients, with 18 patients with probable Alzheimer''s disease, 25 patients with Parkinson''s disease and 17 healthy young and 18 old participants. Uncorrected errors in the AST were selectively increased in Alzheimer''s disease, but not in Parkinson''s disease compared to the control groups. These uncorrected errors were strongly correlated with spatial working memory. There was an increase in the saccade reaction times to targets that were presented simultaneously with the fixation stimulus, compared to the removal of fixation. This ‘gap’ effect (i.e. overlap–gap) saccade reaction time was elevated in the older groups compared to young group, which yielded a strong effect of aging and no specific effect of neurodegenerative disease. Healthy aging, rather than neurodegenerative disease, accounted for the increase in the saccade reaction times to the target that are presented simultaneously with a fixation stimulus. These results suggest that the impairment of inhibitory control in the AST may provide a convenient and putative mark of working memory dysfunction in Alzheimer''s disease.     

Development and application of rodent models for type 2 diabetes

The increasing worldwide incidence of diabetes in adults constitutes a global public health burden. It is predicted that by 2025, India, China and the United States will have the largest number of people with diabetes. According to the 2003 estimates of the International Diabetes Federation, the diabetes mellitus prevalence in the USA is 8.0% and approximately 90-95% of diabetic Americans have type 2 diabetes - about 16 million people. Type 2 diabetes is a complex, heterogeneous, polygenic disease characterized mainly by insulin resistance and pancreatic beta-cell dysfunction. Appropriate experimental models are essential tools for understanding the molecular basis, pathogenesis of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase the risks of type 2 diabetes. Among the animal models available, those developed in rodents have been studied most thoroughly for reasons such as short generation time, inherited hyperglycaemia and/or obesity in certain strains and economic considerations. In this article, we review the current status of most commonly used rodent diabetic models developed spontaneously, through means of genetic engineering or artificial manipulation. In addition to these models, the Psammomys obesus, rhesus monkeys and many other species are studied intensively and reviewed by Shafrir, Bailey and Flatt and Hansen.     

食管鳞癌动物模型的研究进展

建立和应用真实模拟人类疾病的动物模型,从整体水平动态地揭示肿瘤发生机制,从而寻找防治对策和开发治疗新药,是成功开展转化医学研究的关键.食管癌是最高发的恶性肿瘤之一.由于相关活体动物模型研究和开发的相对滞后,对于食管鳞癌的病因、发病机制和相关分子通路缺乏全面系统深入的认识,直接导致无法有针对性地进行早期分子诊断标志物和有...