阿尔茨海默病与糖尿病之间关系的研究进展

阿尔茨海默病(AD)的发病与糖尿病之间关系被逐渐重视。AD患者同时存在脑内胰岛素缺乏与抵抗及外周高胰岛素血症,又被称为"3型糖尿病"。代谢综合征、胰岛素抵抗和糖尿病是发生AD的风险因素,AD发生后又常加重糖尿病发展,形成恶性循环。糖尿病患者的高胰岛素血症使脑内胰岛素降解酶被大量消耗,促进β淀粉样蛋白沉积;β淀粉样蛋白的沉积又加重脑内胰岛素缺乏与抵抗,形成恶性循环,促进AD进展。胰岛素及胰岛素增敏剂之一的过氧化物酶体增殖因子活化受体γ激动剂均被证实治疗AD有效,但可能只针对载脂蛋白E-ε4基因阴性的早期AD患者。同时,糖尿病患者因代谢障碍产生过多的糖化末端产物,导致氧化应激与炎症反应,也加重AD病情。干扰糖化末端产物作用的药物也是未来治疗AD的一个方向。     

阿尔茨海默病遗传基因与胰岛素代谢通路的关联研究进展

阿尔茨海默病(AD)与正常老化的可预测性认知功能障碍不同,AD为多个认知领域早期进行性下降的痴呆。糖尿病和遗传因素可影响AD发病风险。AD和糖尿病具有多种共同的疾病特征,包括胰岛素信号受损,胰岛素抵抗和认知功能障碍等,而进行鼻内吸入胰岛素治疗的AD患者显示部分认知功能症状的改善。多中心全基因组关联研究发现多个基因位点与AD风险相关。文中就近年来基于胰岛素代谢通路与AD遗传基因研究进展进行综述。     

胰岛素及胰岛素抵抗与阿尔茨海默病

胰岛素在中枢神经系统的代谢、调节作用与阿尔茨海默病(AD)发病的关系日益受到重视,胰岛素抵抗(IR)对阿尔茨海默病发病的影响成为研究的热点.其主要机制为胰岛素抵抗促进tau蛋白磷酸化和加重邮Aβ的神经毒性作用,此过程与脑部胰岛素、胰岛素样生长因子所介导的信号系统紊乱有关,胰岛素信号转导在调节和控制神经细胞能量代谢中起着关键作用.随着对胰岛素及胰岛素抵抗与阿尔茨海默病关系的研究深入,希望能对阿尔茨海默病提供更好的预防和治疗措施.     

阿尔茨海默病与心脏类疾病的关系研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种致死性神经退行性疾病.传统学说认为AD与β-淀粉样蛋白(Aβ)学说、tau蛋白学说、细胞周期调节蛋白障碍、氧化应激、炎性机制关系密切.近年来研究表明心脏类疾病还在AD的发病机制中起着关键的作用,与心衰、冠心病、房颤、心脏瓣膜疾病等关系密切.此外,传统医学心主神明,理论依据丰富且源远流长,验证了二者的联系密切.这些对于重新认识AD及其发病机制可能有新的突破,未来随着研究的深入将有较大的科研及临床指导意义.     

阿尔茨海默病中线粒体轴突转运障碍的发生机制

阿尔茨海默病(AD)是一种中枢神经退行性疾病, 其发病机制目前尚不明确。近年来有研究表明, 线粒体轴突转运障碍可能参与AD的进程。正常的线粒体轴突转运过程主要由微管、分子马达和连接蛋白参与, 而AD的早期病理改变可以通过干扰这些蛋白来损伤线粒体轴突转运, 如积聚的β-淀粉样蛋白(Aβ)会损害分子马达的功能, 异常修饰的Tau蛋白会降低微管的稳定性, 突变型早老蛋白-1(PS1)可以通过激活糖原合成酶激酶3β(GSK-3β)来诱导部分相关蛋白的磷酸化, 使线粒体轴突转运出现障碍, 导致突触功能失调。本文围绕AD中线粒体轴突转运障碍可能的发生机制进行综述, 以期为AD的治疗提供新思路。     

抗氧化剂对阿尔茨海默症自噬的调控作用及机制

<正>神经退行性疾病阿尔茨海默症(Alzheimer disease,AD)的特点之一是大量错误折叠的蛋白在神经细胞中异常聚集,引发多种神经功能障碍。自噬是细胞的一种饥饿应答,通过溶酶体或液泡将衰老或受损的细胞器以及形态、功能异常的大分子降解以循环利用,维持细胞内环境相对稳定的生理过程。因此,在AD的早期,自噬通过清除错误折叠、异常聚集的蛋白而具有重要的保护作用。然而,在AD的晚期,过度激活的自噬会导致细胞的损伤而引起疾病的恶化,因此,研究自噬在AD发病过程中的作用与机制对于疾病的治疗具有重要作用。     

胰岛素降解酶基因与阿尔茨海默病的关系

阿尔茨海默病(AD)是老年人智能损害的最常见原因,β淀粉样蛋白毒性学说是其发病机制中的主要学说.胰岛素降解酶(IDE)可以降解胰岛素和β淀粉样蛋白,因此与2型糖尿病和AD密切相关.IDE基因位于10号染色体上,调控着β淀粉样蛋白的降解与清除.近来的研究提示IDE基因与散发性AD相关.本文就IDE基因与AD的关系作一综述.     

β淀粉样蛋白在阿尔茨海默病中所致的细胞内毒性作用

阿尔茨海默病(ALzheimer disease,AD)是一种以进行性智能减退为特征的神经系统退行性疾病.其病因和发病机制尚未完全明了,多种因素的共同作用是其特点之一,而B淀粉样蛋白(β amyloid protein,AB)的神经毒作用长期以来被公认是多种因素导致AD发病的共同通路[1].关于AB在AD发病过程中的毒性作用机制,传统理论认为AB过量产生并在细胞外沉积是导致AD发生的关键.然而新近研究发现细胞外Aβ沉积只是其对细胞产生毒性作用的结果,细胞内Aβ的蓄积才是导致细胞毒性作用的根本因素;另外还有研究认为Aβ在AD发病过程中所导致的毒性作用是一个动态的过程,是由细胞内到细胞外逐渐发展的 [2],本文就将对此综述如下.     

Klotho参与阿尔兹海默病发病的研究进展

Klotho （KL）蛋白是由抗衰老基因KL编码的单次跨膜蛋白,是一种在细胞代谢和稳态维持中起着关键作用的循环因子。用Klotho蛋白对神经元进行预处理,可以减轻与阿尔茨海默病（AD）发病机制密切相关的毒性β淀粉样蛋白和谷氨酸盐引起的神经元损伤,提示Klotho蛋白在AD发病过程中具有神经保护作用。最近研究发现,AD患者脑脊液中Klotho蛋白水平明显下调,而过表达KL基因的AD小鼠模型的认知功能明显改善,且该作用与其抗衰老作用无关。在AD早期,提高Klotho蛋白水平可作为一种治疗策略,防止病情恶化,改善AD患者的预后。由此可见Klotho与AD发病密切相关。     

阿尔茨海默病中内质网应激与Tau蛋白相关作用的研究进展

阿尔茨海默病（AD）是老年性高发的神经退行性疾病,严重影响人们生活质量并带来沉重 的经济负担。AD 的主要病理特征为由tau 蛋白异常磷酸化引起的神经原纤维缠结和由β 淀粉样蛋白 异常聚集形成的老年斑。近年来的研究发现,tau 蛋白的错误折叠及聚集与内质网应激相互作用,在AD 病理机制中起着重要的作用。现通过对内质网应激在AD 发病中的作用机制和tau 蛋白在AD 发病过程 中的病理机制的梳理,探讨内质网应激与tau 蛋白之间可能的关系,以期为AD 发病机制及新靶点药物 的研发和治疗提供新的思路和可能。     

Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease

A number of well-designed epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link, including insulin and insulin resistance, inflammatory cytokines, and oxidative stress. Obesity or physical inactivity might also influence AD through effects on hypertension, insulin sensitivity or inflammation. Typical AD pathology, such as amyloid-beta deposits, might be exacerbated by insulin dysregulation, T2DM itself, or microvascular disease that is a consequence of T2DM. T2DM patients are not routinely evaluated for cognitive outcomes, and cognitive impairment in T2DM is rarely treated. Similarly, AD patients are not routinely evaluated for T2DM or hyperinsulinemia. Current treatments for AD have only modest benefits, and several drugs that target metabolic and inflammatory pathways are being evaluated, most notably the statins, which reduce LDL and inflammation but might not influence amyloid- deposition, an important precursor for AD. Although some evidence supports a potentially important role for peroxisome proliferative activated receptor agonists such as glitazones, at present there are no published randomized clinical trials in AD patients of any drugs that target insulin or insulin resistance. Clinical implications of the T2DM-AD link include cognitive evaluations of patients with T2DM, and potential benefits for such patients through treatment with statins or diabetes drugs that target insulin.     

Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease

Interest in characterizing the role of impaired insulin actions in Alzheimer's disease (AD) and vascular dementia is growing exponentially. This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. The various experimental animal models generated by over-expression, mutation, or depletion of genes that are critical to the insulin or IGF signaling cascades are summarized, noting the degrees to which they reproduce the histopathological, biochemical, molecular, or behavioral abnormalities associated with AD. Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. The extant literature did not resolve whether the CNS insulin resistance in AD represents a local disease process, or complication/extension of peripheral insulin resistance, i.e. chronic hyperglycemia, hyperinsulinemia, and Type 2 diabetes mellitus. The available epidemiological data are largely inconclusive with regard to the contribution of Type 2 diabetes mellitus to cognitive impairment and AD-type neurodegeneration. A major conclusion drawn from this review is that there is a genuine need for thorough and comprehensive study of the neuropathological changes associated with diabetes mellitus, in the presence or absence of superimposed AD or vascular dementia. Strategies for intervention may depend entirely upon whether the CNS disease processes are mediated by peripheral, central, or both types of insulin resistance.     

Diabetes Type II: A Risk Factor for Depression–Parkinson–Alzheimer?

There is ample evidence that impairments in the hypothalamic–pituitary–adrenal (HPA) axis are of etiopathobiochemical importance in a subgroup of patients with “depression”, causing hypercortisolaemia as major metabolic effect. Chronic hypercortisolaemia causes insulin resistance. Therefore, it is not surprising that epidemiological studies demonstrate an association of “depression” with diabetes type II and vice versa. Chronic stress and hypercortisolaemia are conditions, which have been suggested to be causal for Alzheimer’s disease (AD) as brain insulin resistance is associated with β-Amyloid-accumulation and hyperphosphorylation of tau-protein. Depression is one of the significant symptomatology preceding AD. It is however, not known whether “depression” associated with hypercortisolaemia is the subgroup at risk for AD. In contrast to a subgroup of “depression” and to AD, in Parkinson’s disease (PD) there is only weak evidence for an association with diabetes type II and insulin resistance. As “depression” is preceding PD in up to half of such patients, it remains to be elucidated whether this is a subgroup of depressed patients, which is not associated with disturbances of the HPA axis and hypercortisolaemia. Improved clinical and biochemical/molecular knowledge about “depression” associated with AD and PD in comparison to “pure” depression might lead to improved therapeutic strategies and even drug development focusing subtypes of “depression”.     

Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer's disease

In Alzheimer's disease (AD), brain insulin and insulin-like growth factor (IGF) resistance and deficiency begin early, and worsen with severity of disease. The factors mediating progression of brain insulin/IGF resistance in AD are not well understood. We hypothesize that AD progression is mediated via negative cross-talk that promotes toxic ceramide generation and endoplasmic reticulum (ER) stress. The rationale is that insulin resistance dysregulates lipid metabolism and promotes ceramide accumulation, and thereby increases inflammation and stress. Consequences include disruption of cytoskeletal function and AβPP-Aβ secretion. The present study correlates AD stage with activation of pro-ceramide genes, ceramide levels, and molecular indices of ER stress in postmortem human brain tissue. The results demonstrated that in AD, brain insulin/IGF resistance was associated with constitutive activation of multiple pro-ceramide genes, increased ceramide levels, and increased expression of pro-ER stress pathway genes and proteins. Expression of several pro-ceramide and pro-apoptotic ER stress pathway molecules increased with AD severity and brain insulin/IGF resistance. In contrast, ER stress molecules that help maintain homeostasis with respect to unfolded protein responses were mainly upregulated in the intermediate rather than late stage of AD. These findings support our hypothesis that in AD, a triangulated mal-signaling network initiated by brain insulin/IGF resistance is propagated by the dysregulation of ceramide and ER stress homeostasis, which themselves promote insulin resistance. Therefore, once established, this reverberating loop must be targeted using multi-pronged approaches to disrupt the AD neurodegeneration cascade.     

Insulin resistance and Alzheimer's disease: molecular links & clinical implications

Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimer's disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the blood-brain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming full-blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Abeta) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3beta activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulin's actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition-enhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.     

Role of insulin metabolism disturbances in the development of Alzheimer disease: mini review

Alzheimer disease (AD) is the most common form of dementia. Different pathogenic processes have been studied that underlie characteristic changes of AD, including A beta protein aggregation, tau phosphorylation, neurovascular dysfunction, and inflammatory processes. Insulin exerts pleiotropic effects in neurons, such as the regulation of neural proliferation, apoptosis, and synaptic transmission. In this setting, any disturbance in the metabolism of insulin in the central nervous system (CNS) may put unfavorable effects on CNS function. It seems that disturbances in insulin metabolism, especially insulin resistance, play a role in most pathogenic processes that promote the development of AD. In this article, the relationships of disturbances in the metabolism of insulin in CNS with A beta peptides aggregation, tau protein phosphorylation, inflammatory markers, neuron apoptosis, neurovascular dysfunction, and neurotransmitter modulation are discussed, and future research directions are provided.     

Insulin: An Emerging Treatment for Alzheimer’s Disease Dementia?

Accumulating evidence indicates a role for metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). It is widely reported that Type 2 diabetes (T2D) increases the risk of developing AD, and several postmortem analyses have found evidence of insulin resistance in the AD brain. Thus, insulin-based therapies have emerged as potential strategies to slow cognitive decline in AD. The main methods for targeting insulin to date have been intravenous insulin infusion, intranasal insulin administration, and use of insulin sensitizers. These methods have elicited variable results regarding improvement in cognitive function. This review will discuss the rationale for targeting insulin signaling to improve cognitive function in AD, the results of clinical studies that have targeted insulin signaling, and what these results mean for future studies of the role of insulin-based therapies for AD.     

Cerebrospinal fluid levels of insulin in patients with Alzheimer's disease

OBJECTIVES: Some previous reports suggested a potential role of insulin in memory and in the pathophysiology of Alzheimer's disease (AD). We assessed the cerebrospinal fluid (CSF) levels of insulin in patients with AD and in age and sex-matched controls trying to elucidate whether this value could be related with the risk or severity of AD. PATIENTS AND METHODS: We measured the CSF insulin levels in 27 patients with AD and 16 matched controls using a RadioImmunoanalysis method. RESULTS: CSF insulin levels did not differ significantly between AD-patient and control groups. These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. CONCLUSION: These results suggest that CSF insulin concentrations are not related with the risk or severity of AD.     

Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease

Alzheimer's disease (AD) is associated with major impairments in insulin and insulin-like growth factor (IGF) gene expression and signaling in the brain. These abnormalities increase with severity of dementia, and are associated with deficiencies in energy metabolism and acetylcholine homeostasis. The co-existence of brain insulin/IGF deficiency and resistance suggests that AD may represent a brain-specific form of diabetes, i.e. Type 3 diabetes. This hypothesis is supported by the findings in an experimental animal model in which intracerebral (ic) Streptozotocin (STZ) was used to deplete brain and not pancreatic insulin. The ic-STZ treatment produced brain-specific insulin depletion and insulin resistance are associated with progressive neurodegeneration that shares many features in common with AD. We now demonstrate that early treatment with peroxisome-proliferator activated receptor agonists can effectively prevent ic-STZ-induced neurodegeneration and its associated deficits in learning and memory. These effects were mediated by increased binding to insulin receptors, reduced levels of oxidative stress and tau phosphorylation, and increased choline acetyltransferase expression in the brain, suggesting that insulin sensitizer agents may have therapeutic efficacy in early AD.