Role of Insulin Resistance in the Alzheimer's Disease Progression

Recent studies continue to find evidence linking Type 2 diabetes (T2D) with Alzheimer's disease (AD), the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. Insulin resistance or dysfunction of insulin signaling is a universal feature of T2D, the main culprit for altered glucose metabolism and its interdependence on cell death pathways, forming the basis of linking T2D with AD as it may exacerbate Aβ accumulation, tau hyperphosphorylation and devastates glucose transportation, energy metabolism, hippocampal framework and promulgate inflammatory pathways. The current work demonstrates the basic mechanisms of the insulin resistance mediates dysregulation of bioenergetics and progress to AD as a mechanistic link between diabetes mellitus and AD. This work also aimed to provide a potential and feasible zone to succeed in the development of therapies in AD by enhanced hypometabolism and altered insulin signaling.

     

Mental Rotation of Faces in Healthy Aging and Alzheimer's Disease

Background

Previous research has shown that individuals with Alzheimer''s disease (AD) develop visuospatial difficulties that affect their ability to mentally rotate objects. Surprisingly, the existing literature has generally ignored the impact of this mental rotation deficit on the ability of AD patients to recognize faces from different angles. Instead, the devastating loss of the ability to recognize friends and family members in AD has primarily been attributed to memory loss and agnosia in later stages of the disorder. The impact of AD on areas of the brain important for mental rotation should not be overlooked by face processing investigations – even in early stages of the disorder.

Methodology/Principal Findings

This study investigated the sensitivity of face processing in AD, young controls and older non-neurological controls to two changes of the stimuli – a rotation in depth and an inversion. The control groups showed a systematic effect of depth rotation, with errors increasing with the angle of rotation, and with inversion. The majority of the AD group was not impaired when faces were presented upright and no transformation in depth was required, and were most accurate when all faces were presented in frontal views, but accuracy was severely impaired with any rotation or inversion.

Conclusions/Significance

These results suggest that with the onset of AD, mental rotation difficulties arise that affect the ability to recognize faces presented at different angles. The finding that a frontal view is “preferred” by these patients provides a valuable communication strategy for health care workers.     

Cyclic GMP and Nitric Oxide Synthase in Aging and Alzheimer's Disease

Cyclic guanosine monophosphate (cGMP) is an important secondary messenger synthesized by the guanylyl cyclases which are found in the soluble (sGC) and particular isoforms. In the central nervous system, the nitric oxide (NO)-sensitive sGC isoform is the major enzyme responsible for cGMP synthesis. Phosphodiesterases (PDEs) are enzymes for hydrolysis of cGMP in the brain, and they are mainly isoforms 2, 5, and 9. The NO/cGMP signaling pathway has been shown to play an important role in the process underlying learning and memory. Aging is associated with an increase in PDE expression and activity and a decrease in cGMP concentration. In addition, aging is also associated with an enhancement of neuronal NO synthase, a lowering of endothelial, and no alteration in inducible activity. The observed changes in NMDA receptor density along with the Ca²⁺/NO/cGMP pathway underscore the lower synaptic plasticity and cognitive performance during aging. This notion is in agreement with last data indicating that inhibitors of PDE2 and PDE9 improve learning and memory in older rats. In this review, we focus on recent studies supporting the role of Ca²⁺/NO/cGMP pathway in aging and Alzheimer's disease.     

阿尔茨海默病的磁共振成像研究进展

阿尔茨海默病(Alzheimer disease,AD)是最为常见的获得性脑部变性性疾病,本世纪初,德国神经病理学家Alzheimer首先报道一例进行性痴呆以来,该病已经引起医学界的广泛关注.随着世界人口老龄化进程的加快,该病的患病人口数量正在逐年增加,成为导致老年痴呆的主要原因.但是由于该病的病因复杂,而且临床和实验室检查缺乏足够的特异性,使其病变早期的诊断准确率不高,此外,由于其发展过程缓慢,往往缺乏早期无创敏感的诊断方法.海马结构和功能的改变与阿尔茨海默病的发生发展密切相关,磁共振成像技术的和计算机图像处理技术的发展,提供了一种无创伤性的体外测量颅内结构的方法,而且测量结果准确可靠.随着MRI测量技术地不断改进,软件开发及临床研究地不断深入,通过其对与海马各种相关疾病的认识将不断提高,从而为临床疾病的诊断、鉴别诊断、分期、治疗和预后提供了更多有重要价值的信息.本文欲通过对近年来海马结构的磁共振研究进行综述,探讨阿尔茨海默病的磁共振成像进展.     

Reactive Synaptogenesis in Aging and Alzheimer's Disease: Lessons Learned in the Cotman Laboratory

Early experiments resulting in partial deafferentation of the rodent hippocampus demonstrated a robust reactive plasticity response that includes the replacement of lost synaptic contacts. Similar experiments carried out in the hippocampus of aged animals produced an alteration in the temporal sequence of the reactive plasticity response and a slowing of synaptic replacement. In Alzheimer's disease, one observes a marked reduction in the number of synaptic contacts in important association areas of the cortex and hippocampus. This reduction may be the result of an altered reactive plasticity response.     

Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model

Alzheimer''s disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks of Alzheimer''s disease. The central component of neuritic plaques is a small filamentous protein called amyloid β protein (Aβ)¹, which is derived from sequential proteolytic cleavage of the beta-amyloid precursor protein (APP) by β-secretase and γ-secretase. The amyloid hypothesis entails that Aγ-containing plaques as the underlying toxic mechanism in AD pathology². The postmortem analysis of the presence of neuritic plaque confirms the diagnosis of AD. To further our understanding of Aγ neurobiology in AD pathogenesis, various mouse strains expressing AD-related mutations in the human APP genes were generated. Depending on the severity of the disease, these mice will develop neuritic plaques at different ages. These mice serve as invaluable tools for studying the pathogenesis and drug development that could affect the APP processing pathway and neuritic plaque formation. In this protocol, we employ an immunohistochemical method for specific detection of neuritic plaques in AD model mice. We will specifically discuss the preparation from extracting the half brain, paraformaldehyde fixation, cryosectioning, and two methods to detect neurotic plaques in AD transgenic mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thiofalvin S staining method.     

阿尔茨海默病树鼩模型建立的探索

目的探索建立树鼩阿尔茨海默病(AD)动物模型的可行性。方法将30只成年雄性树鼩Tupaia belangeri随机分成3组,模型组腹腔注射D-半乳糖(D-gal)造成急性衰老后,对树鼩双侧海马内一次性注射β淀粉样蛋白1~42片段(Aβ1~42)和鹅膏蕈氨酸(IBO)的混合液,对照(生理盐水)组将所有药物替换为等剂量生理盐水,空白组不做处理。用Morris水迷宫对3组树鼩进行行为学测试,用苏木精-伊红染色法和镀银染色法进行病理检测分析。结果 Morris水迷宫测试结果提示,模型树鼩出现了明显的学习记忆功能障碍。病理检测结果显示,模型组脑海马区出现明显胶质细胞增生和神经纤维缠结。对照组和空白组无明显病理改变。结论腹腔注射D-gal,双侧海马注射Aβ1~42和IBO混合液的方法可以造成树鼩学习记忆能力下降,并出现神经胶质细胞增生和神经纤维缠结,是一种可行的树鼩AD模型造模方法。     

Phosphoproteomic Profiling of Selenate-Treated Alzheimer's Disease Model Cells

The reversible phosphorylation of proteins regulates most biological processes, while abnormal phosphorylation is a cause or consequence of many diseases including Alzheimer''s disease (AD). One of the hallmarks of AD is the formation of neurofibrillary tangles (NFTs), which is composed of hyperphosphorylated tau proteins. Sodium selenate has been recently found to reduce tau hyperphosphorylation and NFTs formation, and to improve spatial learning and motor performance in AD mice. In the current study, the phosphoproteomics of N2aSW cells treated with selenate were investigated. To avoid missing low-abundance phosphoproteins, both the total proteins of cells and the phosphor-enriched proteins were extracted and subjected to the two-dimensional gel electrophoresis with Pro-Q diamond staining and then LC-MS/MS analysis. A total of 65 proteins were altered in phosphorylation level, of which 39 were up-regulated and 26 were down-regulated. All identified phosphoproteins were bioinformatically annotated according to their physiochemical features, subcellular location, and biological function. Most of these significantly changed phosphoproteins are involved in crucial neural processes such as protesome activity, oxidative stress, cysteine and methionine metabolism, and energy metabolism. Furthermore, decreases were found in homocysteine, phosphor-tau and amyloid β upon selenate treatment. Our results suggest that selenate may intervene in the pathological process of AD by altering the phosphorylation of some key proteins involved in oxidative stress, energy metabolism and protein degradation, thus play important roles in maintaining redox homeostasis, generating ATP, and clearing misfolded proteins and aggregates. The present paper provides some new clues to the mechanism of selenate in AD prevention.     

Aging, Amyloid, and Alzheimer's Disease: A Perspective in Honor of Carl Cotman

Deciphering the molecular basis of synaptic dysfuction in Alzheimer's disease (AD) has engaged the attention of scientists with diverse backgrounds and interests. The synthesis of experimental findings from neuropathology, biochemistry, genetics, animal modeling and even immunology, has provided a plausible model for the pathogenesis of the disorder. While not universally accepted, the so-called amyloid (or Aß) hypothesis of AD is well supported scientifically and predicts several specific targets for therapeutic intervention. Some of these are now reaching the clinic, providing the final and most important test for this hypothetical mechanism of disease.     

Dietary Manipulation and Social Isolation Alter Disease Progression in a Murine Model of Coronary Heart Disease

Background

Mice with a deficiency in the HDL receptor SR-BI and low expression of a modified apolipoprotein E gene (SR-BI KO/ApoeR61^h/h) called ‘HypoE’ when fed an atherogenic, ‘Paigen’ diet develop occlusive, atherosclerotic coronary arterial disease (CHD), myocardial infarctions (MI), and heart dysfunction and die prematurely (50% mortality ∼40 days after initiation of this diet). Because few murine models share with HypoE mice these cardinal, human-like, features of CHD, HypoE mice represent a novel, small animal, diet-inducible and genetically tractable model for CHD. To better describe the properties of this model, we have explored the effects of varying the composition and timing of administration of atherogenic diets, as well as social isolation vs. group housing, on these animals.

Methodology/Principal Findings

HypoE mice were maintained on a standard lab chow diet (control) until two months of age. Subsequently they received one of three atherogenic diets (Paigen, Paigen without cholate, Western) or control diet for varying times and were housed in groups or singly, and we determined the plasma cholesterol levels, extent of cardiomegaly and/or survival. The rate of disease progression could be reduced by lowering the severity of the atherogenic diet and accelerated by social isolation. Disease could be induced by Paigen diets either containing or free of cholate. We also established conditions under which CHD could be initiated by an atherogenic diet and then subsequently, by replacing this diet with standard lab chow, hypercholesterolemia could be reduced and progression to early death prevented.

Conclusions/Significance

HypoE mice provide a powerful, surgery-free, diet-‘titratable’ small animal model that can be used to study the onset of recovery from occlusive, atherosclerotic CHD and heart failure due to MI. HypoE mice can be used for the analysis of the effects of environment (diet, social isolation) on a variety of features of cardiovascular disease.     

Ornithine Decarboxylase in Human Brain: Influence of Aging, Regional Distribution, and Alzheimer's Disease

Abstract: Although experimental animal data have implicated ornithine decarboxylase, a key regulatory enzyme of polyamine biosynthesis, in brain development and function, little information is available on this enzyme in normal or abnormal human brain. We examined the influence, in autopsied human brain, of postnatal development and aging, regional distribution, and Alzheimer's disease on the activity of ornithine decarboxylase. Consistent with animal data, human brain ornithine decarboxylase activity was highest in the perinatal period, declining sharply (by ∼60%) during the first year of life to values that remained generally unchanged up to senescence. In adult brain, a moderately heterogeneous regional distribution of enzyme activity was observed, with high levels in the thalamus and occipital cortex and low levels in cerebellar cortex and putamen. In the Alzheimer's disease group, mean ornithine decarboxylase activity was significantly increased in the temporal cortex (+76%), reduced in occipital cortex (−70%), and unchanged in hippocampus and putamen. In contrast, brain enzyme activity was normal in patients with the neurodegenerative disorder spinocerebellar ataxia type I. Our demonstration of ornithine decarboxylase activity in neonatal and adult human brain suggests roles for ornithine decarboxylase in both developing and mature brain function, and we provide further evidence for the involvement of abnormal polyamine system activity in Alzheimer's disease.     

A Model for a Proportional Treatment Effect on Disease Progression

Treatments intended to slow the progression of chronic diseases are often hypothesized to reduce the rate of further injury to a biological system without improving the current level of functioning. In this situation, the treatment effect may be negligible for patients whose disease would have been stable without the treatment but would be expected to be an increasing function of the progression rate in patients with worsening disease. This article considers a variation of the Laird Ware mixed effects model in which the effect of the treatment on the slope of a longitudinal outcome is assumed to be proportional to the progression rate for patients with progressive disease. Inference based on maximum likelihood and a generalized estimating equations procedure is considered. Under the proportional effect assumption, the precision of the estimated treatment effect can be increased by incorporating the functional relationship between the model parameters and the variance of the outcome variable, particularly when the magnitude of the mean slope of the outcome is small compared with the standard deviation of the slopes. An example from a study of chronic renal disease is used to illustrate insights provided by the proportional effect model that may be overlooked with models assuming additive treatment effects.     

Classification of Structural MRI Images in Alzheimer's Disease from the Perspective of Ill-Posed Problems

Background

Machine learning neuroimaging researchers have often relied on regularization techniques when classifying MRI images. Although these were originally introduced to deal with “ill-posed” problems it is rare to find studies that evaluate the ill-posedness of MRI image classification problems. In addition, to avoid the effects of the “curse of dimensionality” very often dimension reduction is applied to the data.

Methodology

Baseline structural MRI data from cognitively normal and Alzheimer''s disease (AD) patients from the AD Neuroimaging Initiative database were used in this study. We evaluated here the ill-posedness of this classification problem across different dimensions and sample sizes and its relationship to the performance of regularized logistic regression (RLR), linear support vector machine (SVM) and linear regression classifier (LRC). In addition, these methods were compared with their principal components space counterparts.

Principal Findings

In voxel space the prediction performance of all methods increased as sample sizes increased. They were not only relatively robust to the increase of dimension, but they often showed improvements in accuracy. We linked this behavior to improvements in conditioning of the linear kernels matrices. In general the RLR and SVM performed similarly. Surprisingly, the LRC was often very competitive when the linear kernel matrices were best conditioned. Finally, when comparing these methods in voxel and principal component spaces, we did not find large differences in prediction performance.

Conclusions and Significance

We analyzed the problem of classifying AD MRI images from the perspective of linear ill-posed problems. We demonstrate empirically the impact of the linear kernel matrix conditioning on different classifiers'' performance. This dependence is characterized across sample sizes and dimensions. In this context we also show that increased dimensionality does not necessarily degrade performance of machine learning methods. In general, this depends on the nature of the problem and the type of machine learning method.     

Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease

Brain mitochondrial dysfunction is hallmark pathology of Alzheimer’s disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Aβ), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin-mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning & memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Aβ-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD.     

磁共振技术在轻度认知障碍与阿尔茨海默病中的研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是当今老年人最常见的一种原发性神经退行性疾病。其主要病理学特征表现为神经元的脱失、神经纤维缠结及老年斑形成。轻度认知障碍(mild cognitive impairment,MCI)被认为是AD及其他老年痴呆症的前驱阶段,可进一步转化成AD,且MCI与AD有着相似的病理变化。随着MCI和AD患病数的逐年增加,其给患者家属及社会增添了巨大负担,因此,对MCI和AD作出早期诊断变得尤为重要。然而,MCI和AD早期的临床表现并不突出,且实验室检查也缺乏足够的特异性,当临床医生做出明确诊断时,多数患者已处于AD的中晚期。近年来,随着磁共振技术的不断发展,多种磁共振技术已广泛地应用于MCI和AD的研究中,并为MCI及AD的早期诊断提供了重要的影像学依据。本文分别从结构性磁共振(s MRI)、静息态f MRI、磁共振弥散张量成像(DTI)、磁共振波谱成像(MRS)、磁敏感加权成像(SWI)及MRI分子影像几个方面,阐述多种磁共振技术在MCI和AD研究中的进展。     

Periodontal Disease and Aging

Periodontitis is a chronic disease of humans and animals which becomes more prevalent and severe with increasing age. The prevalent interpretation of the strong correlation between periodontal disease and age is that age merely occurs simultaneously during the extended time that irreversible loss of tooth support results from the accumulative effects of plaque and calculus. In both animals and humans, changes in the periodontium occur with age and are similar to those seen in the same type of tissues elsewhere in the body. To date, it is not clear to what extent these aging changes affect the response of the periodontium to local irritants. At all ages, periodontitis is more severe in mouths with abundant debris and calculus. However, even when these accumulations are minimal, periodontitis becomes more severe with age. Yet, not all elderly, and especially not all teeth in the elderly, suffer from destructive periodontal disease. The periodontium of old animals and humans retains the ability to respond adequately to changes in occlusal forces and to wounding, but the response is delayed in onset and duration. As well, the elderly are likely to suffer from other chronic diseases which may affect the periodontium and its therapy.     

Olfactory Functions in Parkinson's Disease and Alzheimer's Disease

The aim of this investigation was to compare olfactory functionsof patients suffering from Parkinson's disease (PD) and Alzheimer'sdisease (AD). Olfactory threshold, odor identification abilityand odor memory performance were assessed in 21 non-dementedPD patients and in 22 AD patients. Both patient groups wereimpaired in relation to an age-matched control group for themeasure of odor identification. AD patients showed a higherolfactory threshold and poorer odor memory performance. ChemSenses 22: 105–110, 1997.     

脑啡肽酶（neprilysin）和阿尔茨海默病

由于阿尔茨海默病 (Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ ,ＡＤ)的病因不明和到目前为止仍缺乏根治的办法 ,加之全世界范围的老龄化和ＡＤ的高发病率 ,一些科学家预言ＡＤ可能是本世纪最可怕的老年病。ＡＤ的数十年的漫长病程一般从 β淀粉样肽 (Ａβ)在脑中沉着开始 ,Ａβ是一个生理性多肽 ,它是淀粉样前体蛋白(ＡＰＰ)的水解产物。它的合成和分解代谢的平衡决定它在体内有一个稳定的水平。研究证明 ,由于基因突变导致的特殊形式的Ａβ的产生增加 50 %就能引起ＡＤ ,Ａβ代谢平衡的轻微改变不仅能影响ＡＤ的病理过程 ,而且能影响这个疾病的发…