Proteomics in animal models of Alzheimer's and Parkinson's diseases

The risk of developing neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) increases with age. AD and PD are the two most common neurodegenerative diseases that currently affect millions of persons within the United States population. While many clues about the mechanisms of these disorders have been uncovered, to date, the molecular mechanisms associated with the cause of these diseases are not completely understood. Furthermore, there are no available cures or preventive treatments for either disorder. Animal models of AD and PD, though not perfect, offer a means to gain knowledge of the basic biochemistry associated with these disorders and with drug efficacy. The field of proteomics which focuses on identifying the dynamic nature of the protein content expressed within a particular cell, tissue, or organism, has provided many insights into these disturbing disorders. Proteomic studies have revealed many pathways that are associated with disease pathogenesis and that may lead to the development of potential therapeutic targets. This review provides a discussion of key findings from AD and PD proteomics-based studies in various animal models of disease.     

Neuroprotective effects of cognitive enrichment

Cognitive enrichment early in life, as indicated by level of education, complexity of work environment or nature of leisure activities, appears to protect against the development of age-associated cognitive decline and also dementia. These effects are more robust for measures of crystallized intelligence than for measures of fluid intelligence and depend on the ability of the brain to compensate for pathological changes associated with aging. This compensatory ability is referred to as cognitive reserve. The cognitive reserve hypothesis suggests that cognitive enrichment promotes utilization of available functions. Alternatively, late life cognitive changes in cognition may be linked to a factor, such as cholinergic dysfunction, that is also present early in life and contributes to the reduced levels of early life cognitive enrichment. Beneficial effects of environmental enrichment early in life have also been observed in rodents and primates. Research with rodents indicates that these changes have structural correlates, which likely include increased synapses in specific brain regions. Dogs also show age-dependent cognitive decline, and both longitudinal and cross-sectional studies indicate that this decline can be attenuated by cognitive enrichment. Furthermore, cognitive enrichment has differential effects, improving some functions more than others. From a neurobiological perspective, behavioral enrichment in the dog may act to promote neurogenesis later in life. This can be distinguished from nutritional interventions with antioxidants, which appear to attenuate the development of neuropathology. These results suggest that a combination of behavioral and nutritional or pharmacological interventions may be optimal for reducing the rate of age-dependent cognitive decline.     

Animal models in the study of Alzheimer's disease and Parkinson's disease: A historical perspective

Alzheimer's disease and Parkinson's disease are two of the most prevalent and disa-bling neurodegenerative diseases globally. Both are proteinopathic conditions and while occasionally inherited, are largely sporadic in nature. Although the advances in our understanding of the two have been significant, they are far from complete and neither diagnosis nor the current practices in treatment and rehabilitation is ad-equately helpful. Animal models have historically found application as testing beds for novel therapeutics and continue to be valuable aids in pharmacological research. This review chronicles the development of those models in the context of Alzheimer's and Parkinson's disease, and highlights the shifting paradigms in studying two human- specific conditions in non- human organisms.     

定量脑电图在帕金森病认知功能障碍中的应用

目的:探讨定量脑电图在帕金森病(PD)认知功能障碍中的应用价值.方法:选择2017年1月至2018年6月江门市中心医院收治的80例PD患者,按照简易智力状态检查量表(MMSE)进行分组,将37例认知功能正常者纳入对照组,将43例认知功能障碍者纳入观察组.对两组患者进行脑电图检查,将两组的MMSE评分、功率谱、(δ+θ)...     

一种新的老年期痴呆大鼠模型的研究

目的:建立一种新的用于老年期痴呆发病机制与防治研究的老年期大鼠模型。方法:雄性Wistar大鼠,双侧颈总动脉永久性结扎(2VO)并腹腔注射D-半乳糖(D-gal)6周(60mg/kg/天),制备老年期痴呆大鼠模型。采用神经电生理(事件相关电位)检测,脑组织切片Bielschowsky改良法银染色、HE染色、海马乙酰胆碱酯酶(AchE)活性检测等方法比较模型鼠和正常对照鼠的差异。结果:与对照组相比,模型组鼠出现白内障改变及明显P300潜伏期延长、脑内AchE活性降低、海马神经元变性、固缩、坏死及神经纤维紊乱等变化。结论:双侧颈兔动脉永久性结扎加D-gal腹腔注射制备的大鼠模型模拟了人类老年期痴呆的发病特点,可用于血管性痴呆、阿尔茨海默病等老年期痴呆的形态、病理生理变化机制及防治措施的基础与临床研究。     

Animal models in infection and inflammation – chance and necessity

In biomedical research, to understand pathogenesis and test innovative therapeutic strategies, animal models of human disease are a bare necessity. We cannot do without them, but could we do better with them? In this issue of the European Journal of Immunology a series of Viewpoints discusses the pros and cons of currently available animal models that address the clinical challenges of immunology in infection and inflammatory diseases.     

Animal models of pre-eclampsia

The cardinal features of human pre-eclampsia, hypertension and proteinuria, are mimicked in animal models. Increasingly, the accuracy of inducing 'pure' systemic endothelial dysfunction is regarded as critical in differentiating mechanisms of pre-eclampsia from other conditions which induce hypertension (e.g. glomerulonephritis, renal denervation or manipulation of the renin-angiotensin system). A recent study in baboons has identified the timing of induction of maternal endothelial damage after acute uteroplacental ischaemia (UPI). The endothelial changes in the glomerulus are indicative of a direct endothelial toxin and mimic the lesions seen in human pre-eclampsia; the extent of hypertension and proteinuria are also similar. This animal model identifies systemic and placental sFLT-1 (soluble fms-like tyrosine kinase-1) as a potential mediator of endothelial damage. This research involving primates with haemomonochorial placentas makes translation of these results to humans very compelling for understanding the mechanisms of human disease. Similar endothelial dysfunction has been identified in baboons treated with anti-inflammatory inhibitors. Similar studies in rodents have identified a relationship between angiotensin II agonistic antibodies, UPI/reduced uteroplacental perfusion pressure, angiogenic markers, and cytokines. We can now identify vasoconstrictive mediators of the hypertensive and endothelial response such as endothelin 1, the renin-angiotensin system, or other hormones such as oestrogens in primate models.     

阿尔茨海默病与血管性痴呆患者认知功能的比较研究

目的 :评价阿尔茨海默病 (AD)和血管性痴呆 (VD)患者认知功能障碍的异同 ;方法 :用简易智力状态检查表 (MMSE)、韦氏记忆量表 (WMS)、日常生活能力量表 (ADL)对 34例AD患者和 4 9例VD患者的认知功能进行测查 ;结果 :(1)MMSE结果表明AD组在短程记忆得分低于VD组 (P <0 .0 1) ,在语言复述得分高于VD组 (P <0 .0 5 ) ;(2 )WMS结果表明AD组在经历 (P <0 .0 5 )、图形再认 (P <0 .0 5 )、理解记忆 (P <0 .0 5 ) ,定向 (P <0 .0 1)得分显著低于VD组 ;(3)ADL结果显示AD组与VD组无显著差异。结论 :AD组和VD组均有记忆障碍 ,AD组受损更为严重并以记忆注意受损为突出 ,VD组相对较轻并以语言复述受损为突出     

Animal models in the investigation of anorexia

Anorexia nervosa (AN) is an eating disorder of unknown origin that most commonly occurs in women and usually has its onset in adolescence. Patients with AN invariably have a disturbed body image and an intense fear of weight gain. There is currently no definitive treatment for this disease, which carries a 20% mortality over 20 years. Development of an appropriate animal model of AN has been difficult, as the etiology of this eating disorder likely involves a complex interaction between genetic, environmental, social, and cultural factors. In this review, we focus on several possible rodent models of AN. In our laboratory, we have developed and studied three different mouse models of AN based on clinical profiles of the disease; separation stress, activity, and diet restriction (DR). In addition, we discuss the spontaneous mouse mutation anx/anx and several mouse gene knockout models, which have resulted in an anorexic phenotype. We highlight what has been learned from each of these models and possibilities for future models. It is hoped that a combination of the study of such models, together with genetic and clinical studies in patients, will lead to more rational and successful prevention/treatment of this tragic, and often fatal, disease.     

Metabolic syndrome, mild cognitive impairment, and progression to dementia. The Italian Longitudinal Study on Aging

We investigated the relationship of metabolic syndrome (MetS) and its individual components with incidence of mild cognitive impairment (MCI) and its progression to dementia in a large longitudinal Italian population-based sample with a 3.5-year follow-up. A total of 2097 participants from a sample of 5632 65-84-year-old subjects from the Italian Longitudinal Study on Aging were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. MCI, dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were classified using current published criteria. Among MCI patients those with MetS (N = 49) had a higher risk of progression to dementia (HR, 4.40; 95% CI, 1.30-14.82) compared with those without MetS (N = 72). After a multivariate adjustment, the risk in MCI patients with MetS approximately doubled (multivariate adjusted HR, 7.80, 95% CI 1.29-47.20) compared with those MCI without MetS. Finally, among non-cognitively impaired individuals there were no significant differences in risks of developing MCI in those who were affected by MetS (N = 608) in comparison with those without MetS (N = 837), as well as excluding those individuals with undernutrition or low inflammatory status with or without undernutrition. In our population, among MCI patients the presence of MetS independently predicted an increased risk of progression to dementia over 3.5 years of follow-up.     

The endocannabinoid pathway in Huntington's disease: a comparison with other neurodegenerative diseases

Endocannabinoids are endogenous agonists of cannabinoid receptors, and comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol are the best-studied members of this class of lipid mediators, and it is now widely accepted that their in vivo concentration and biological activity are largely dependent on a “metabolic control.” Therefore, the proteins that synthesize, transport and degrade endocannabinoids, and that together with the target receptors form the so-called “endocannabinoid system,” are the focus of intense research. This new system will be presented in this review, in order to put in a better perspective the impact of its modulation on Huntington's disease. In particular, the effect of agonists/antagonists of endocannabinoid receptors, or of inhibitors of endocannabinoid metabolism, will be discussed in the context of onset and progression of Huntington's disease, and will be compared with other neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotropic lateral sclerosis. Also the plastic changes of endocannabinoids in multiple sclerosis will be reviewed, as a paradigm of their impact in neuroinflammatory disorders.     

Animal models of fibrodysplasia ossificans progressiva

Fibrodysplasia Ossificans Progressiva is a rare human disease of heterotopic ossification. FOP patients experience progressive development of ectopic bone within fibrous tissues that contributes to a gradual loss of mobility and can lead to early mortality. Due to lack of understanding of the etiology and progression of human FOP, and the fact that surgical interventions often exacerbate FOP disease progression, alternative therapeutic methods are needed, including modeling in animals, to study and improve understanding of human FOP. In this review we provide an overview of the existing animal models of FOP and the key mechanistic findings from each. In addition, we highlight the specific advantages of a new adult zebrafish model, generated by our lab, to study human FOP. Developmental Dynamics 247:279–288, 2018. © 2017 Wiley Periodicals, Inc.     

Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: A meta-analysis

It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ?4 mutation and VaD risk (for ?3/?4 vs. ?3/?3: OR = 1.65, 95% CI = 1.40–1.94, p-value < 0.00001; for ?4/?4 vs. ?3/?3: OR = 3.17, 95% CI = 2.09–4.80, p-value < 0.00001; for ?4 allele vs. ?3 allele: OR = 1.72, 95% CI = 1.40–2.12, p-value < 0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ?4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease

Vascular risk factors have been implicated in the pathogenesis of vascular dementia and Alzheimer's disease. The identification of a novel vascular disease susceptibility locus at 9p21.3 has recently generated great interest. In the present study, we sought to determine whether a common genetic variant (tagged by rs1333049, G/C) in the 9p21.3 locus—that has been previously linked to an increased vascular risk—might influence the susceptibility to vascular dementia (VaD) and late-onset Alzheimer's disease (LOAD). A cohort of 200 VaD patients, 407 LOAD patients and 405 cognitively healthy controls were genotyped for rs1333049 using a fluorogenic 5′ nuclease assay. The frequency of the C allele of rs1333049 was significantly higher in VaD (62.2%, P = 0.005) and LOAD (60.7%, P = 0.004) patients than in controls (53.6%). After adjustment for the APOE ε4 carrier status and other vascular risk factors, the C allele of rs1333049 remained significantly associated with both VaD (OR 1.31, 95% CI 1.07-1.77, P < 0.01) and LOAD (OR 1.28, 95% CI 1.04-1.55, P < 0.01). Altogether, our data indicate for the first time that the C allele of rs1333049 in the vascular disease susceptibility locus is associated with VaD and LOAD, independent of traditional risk factors and the APOE ε4 genotype.     

帕金森病相关基因模型的研究进展

帕金森病(PD)是一种遗传和环境因素共同作用的神经退行性疾病.针对这2大因素,有各种各样的动物模型.转基因动物模型足采用显微注射、电子穿孔、微粒子轰击、病毒载体转染等方法使外源目的 基因在其体内表达的一种动物,利用这种动物建立的模型可以模拟致病基因诱发疾病的过程,在研究疾病的发病机理、基因治疗及药物干预方面有积极作用.主要论述基因工程PD模型的研究进展及其对PD研究的贡献. Abstract： Parkinson's disease(PD) is a kind of degenerative disease caused by both genetic and environ-mental factors. Concerning these two factors, various animal models for parkinson's disease were made for the study. Transgenic animal models were made by the method of microinjection, electronic perforation, particle bom-bardment, virus vector transfection and so on, which can express exogenous target gene. These models imitated the process of Parkinson's desease induced by virulence gene and provided a powerful tool for investigation on e-tiopathogenesis, gene therapy and medical intervention. In this article, we reviewed the progress of genetic models associated with PD and theirs contribution to PD research.     

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.     

Puerarin attenuates cognitive dysfunction and oxidative stress in vascular dementia rats induced by chronic ischemia

Objective: To explored the effects of puerarin on cognitive deficits and tissue oxidative stress and the underlying mechanisms. Methods: 6 to 8 week old male Wistar rats were adopted as experimental animals. Morris water maze (MWM) test was adopted to test the learning and memory function of rats. MDA, glutathione peroxidase and total thiol assessment was done to reflect the oxidative stress in the brain tissue. Cell Counting Kit-8 (CCK8) and flow cytometry (FCM) were performed to examine the cell viability and apoptosis rate. Reactive oxygen species (ROS) generation was determined by the 2’, 7’-dichlorofluorescein diacetate (DCFH-DA) assay. qPCR and Western blot (WB) were adopted to test the molecular function mechanisms of puerarin. Results: Our results indicated a protective effect of puerarin on vascular dementia. Administration of puerarin could improve the impaired learning and memory function. The levels of MDA were partially decreased by puerarin. The levels of glutathione peroxidase and total thiol were partially restored. Cell viability was improved in a dose-dependent pattern (P < 0.05). Cell apoptosis rate was reduced in a dose-dependent pattern (P < 0.05). Puerarin could scavenge ROS generation induced by pre-treatment of hydrogen peroxide. The results showed up-regulated levels of Nrf2, FoxO1, FoxO3 and FoxO4 (P < 0.05). Conclusion: Puerarin is protective on the vascular dementia by reducing oxidative stress and improving learning and memory functions. On the molecular level, Nrf2, FoxO1, FoxO3 and FoxO4 were up regulated by puerarin.     

Animal models of mucosal inflammation and their relation to human inflammatory bowel disease

Animal models of inflammatory bowel disease (IBD) have been useful in the identification of those immune responses uniquely involved in IBD pathogenesis and in defining the important roles of environmental influences, such as normal luminal bacterial flora and the genetic composition of the host, in modifying IBD-associated inflammation. Recent studies have focused particular attention on CD4+ T cells which produce excessive quantities either of Th1 cytokines (IFN-gamma and TNF) directed by IL-12 or of a Th2 cytokine (IL-4), relative to the production of suppressive cytokines such as IL-10 and transforming growth factor beta. Such insights will be extremely beneficial in the development of novel approaches to the control of IBD-type inflammation, such as the use of anticytokine therapies and gene therapy, and finally, in the identification of the genetic abnormalities and the antigens driving the inflammation that underlies the human disease.     

RAGE阻断剂FPS-ZM1减轻异氟醚麻醉诱发老龄大鼠认知功能障碍

目的探讨RAGE阻断剂FPS-ZM1对异氟醚麻醉诱发老龄大鼠认知功能障碍的影响。方法将老龄大鼠60只,随机分为4组(n=15):NS+O2组、NS+ISO组、FPS-ZM1+ISO组及FPS-ZM1+O2组。NS+O2组及NS+ISO组,侧脑室注射无菌0.9%氯化钠溶液10μL,FPS-ZM1+ISO及FPS-ZM1+O2组,侧脑室注射FPS-ZM1 10μL(5 g/L)。侧脑室注射后24 h,NS+O2及FPS-ZM1+O2组吸入含有30%氧气的空氧混合气体4 h,FPS-ZM1+ISO及FPS-ZM1+ISO组吸入2%异氟醚+100%氧气4 h。用Morris水迷宫评测大鼠学习和记忆功能,用免疫组织化学技术观察海马CA1区RAGE及Aβ的表达。结果与NS+O2组相比,NS+ISO组第1~4天逃避潜伏期延长、探索时间缩短、海马CA1区RAGE表达上调、Aβ表达上调。与NS+ISO组相比,FPS-ZM1+ISO组第1~4天逃避潜伏期缩短,探索时间延长,RAGE表达下调、Aβ表达下调。结论 RAGE阻断剂FPS-ZM1可改善异氟醚麻醉诱发老年大鼠认知功能障碍,其机制可能与其抑制海马CA1区Aβ沉积有关。     

Invited Commentary on Animal Models in Psychiatry: Animal Models of Non-conventional Human Behavior

Conventional behavior, of which linguistic behavior is the principal variety, is identified as responses having formal properties that are not determined by the natural properties of stimulus objects, but instead by properties attributed to those objects under the auspices of particular groups. Given the ubiquity of this type of behavior in the repertoires of human beings and its complete absence in those of non-humans, the argument is made that animal models of human disorders, in which disturbances of conventional behaviors constitute defining features, are not sufficiently analogous to these conditions in humans to be pursued with good result. Because conventional behavior of the linguistic type is ubiquitous in the repertoires of normally developed human adults, it is suggested that the behavior of pre-verbal infants and/or non-verbal persons is preferable to that of adults as the phenomenal source for the construction of animal models of human psychological events. The observation and measurement of psychological events is held to be complicated by a number of their characteristics, including their complexity by virtue of whole organism participation, their essential complementarily with stimulus events, and the corrigibility of both form and function over their repeated occurrences, among others. The implications of these features for modeling enterprises are discussed.