Question hard, answer simply: A comment on Storms et al. (2003).

It seems clear that, for whatever reasons, the dementia of the Alzheimer type patient group (as well as other patient groups) exhibits behavior that is different from the normal control group. G. Storms, T. Dirikx, J. Saerens, S. Verstraeten, and P. P. De Deyn (2003) rightfully argue that the observed behavior (similarity judgments) does not tell us the source (cause) of the differences between the 2 groups. Rather, the focus of the study should be placed more on finding the ways the 2 groups are different. They also point out various methodological problems in some of the previous attempts to characterize the nature of the differences. Further methodological issues in G. Storms et al.'s study are examined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Analysis of sub-anatomic diffusion tensor imaging indices in white matter regions of Alzheimer with MMSE score

In this study, an attempt has been made to find the correlation between diffusion tensor imaging (DTI) indices of white matter (WM) regions and mini mental state examination (MMSE) score of Alzheimer patients. Diffusion weighted images are obtained from the ADNI database. These are preprocessed for eddy current correction and removal of non-brain tissue. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (DA) indices are computed over significant regions (Fornix left, Splenium of corpus callosum left, Splenium of corpus callosum right, bilateral genu of the corpus callosum) affected by Alzheimer disease (AD) pathology. The correlation is computed between diffusion indices of the significant regions and MMSE score using linear fit technique so as to find the relation between clinical parameters and the image features. Binary classification has been employed using support vector machine, decision stumps and simple logistic classifiers on the extracted DTI indices along with MMSE score to classify Alzheimer patients from healthy controls. It is observed that distinct values of DTI indices exist for the range of MMSE score. However, there is no strong correlation (Pearson's correlation coefficient ‘r’ varies from 0.0383 to −0.1924) between the MMSE score and the diffusion indices over the significant regions. Further, the performance evaluation of classifiers shows 94% accuracy using SVM in differentiating AD and control. In isolation clinical and image features can be used for prescreening and diagnosis of AD but no sub anatomic region correlation exist between these features set. The discussion on the correlation of diffusion indices of WM with MMSE score is presented in this study.     

阿尔茨海默病药物治疗的研究进展

综述了阿尔茨海默病的药物治疗研究进展,包括乙酰胆碱酯酶抑制剂,NMDA受体拮抗剂,非甾体类抗炎药,抗氧化剂,免疫治疗以及针对Aβ的其它治疗手段等.     

Morphological and chemical studies of pathological human and mice brain at the subcellular level: correlation between light, electron, and nanosims microscopies

Neurodegenerative diseases induce morphological and chemical alterations in well-characterized regions of the brain. Understanding their pathological processes requires the use of methods that assess both morphological and chemical alterations in the tissues. In the past, microprobe approaches such as scanning electron microscopy combined with an X-ray spectrometer, Proton induced X-ray emission, secondary ion mass spectrometry (SIMS), and laser microprobe mass analysis have been used for the study of pathological human brain with limited success. At the present, new SIMS instruments have been developed, such as the NanoSIMS-50 ion microprobe, that allow the simultaneous identification of five elements with high sensitivity, at subcellular spatial resolution (about 50-100 nm with the Cs(+) source and about 150-200 nm with O(-) source). Working in scanning mode, 2D distribution of five elements (elemental maps) can be obtained, thus providing their exact colocalization. The analysis can be performed on semithin or ultrathin embedded sections. The possibility of using transmission electron microscopy and SIMS on the same ultrathin sections allows the correlation between structural and analytical observations at subcellular and ultrastructural level to be established. Our observations on pathological brain areas allow us to establish that the NanoSIMS-50 ion microprobe is a highly useful instrument for the imaging of the morphological and chemical alterations that take place in these brain areas. In the human brain our results put forward the subcellular distribution of iron-ferritin-hemosiderin in the hippocampus of Alzheimer disease patients. In the thalamus of transgenic mice, our results have shown the presence of Ca-Fe mineralized amyloid deposits.     

The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer’s disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.     

β-淀粉样多肽自聚集抑制剂的电化学筛选方法研究

β-淀粉样多肽（Amyloidbeta,Aβ）的聚集物具有神经细胞毒性,可导致神经元凋亡,从而诱导阿尔茨海默症（Alzheimer’s disease,AD）的发生。能够抑制AB自聚集行为的化合物称为AB自聚集抑制剂。该抑制剂可抑制Aβ有毒聚集物的产生,从而降低Aβ所引起的神经细胞毒性,对AD病有一定的治疗效果。因此。筛选AB自聚集抑制剂对于AD的治疗有着重要的意义。在数以千万计的化合物中,要筛选出对Aβ自聚集有抑制效果的化合物需要借助众多的仪器和研究方法。该文总结了筛选AB自聚集抑制剂的几种方法．重点综述了几种低成本、快速、灵敏的电化学筛选方法。Aβ自聚集抑制剂的筛选对临床上AD病的治疗提供了理论基础,为治疗AD病这一复杂科学问题的研究起到了促进作用。     

Effects of Combining Biofactors on Bioenergetic Parameters,Aβ Levels and Survival in Alzheimer Model Organisms

Increased amyloid beta (Aβ) levels and mitochondrial dysfunction (MD) in the human brain characterize Alzheimer disease (AD). Folic acid, magnesium and vitamin B6 are essential micro-nutrients that may provide neuroprotection. Bioenergetic parameters and amyloid precursor protein (APP) processing products were investigated in vitro in human neuroblastoma SH-SY5Y-APP695 cells, expressing neuronal APP, and in vivo, in the invertebrate Caenorhabditis elegans (CL2006 & GMC101) expressing muscular APP. Model organisms were incubated with either folic acid and magnesium-orotate (ID63) or folic acid, magnesium-orotate and vitamin B6 (ID64) in different concentrations. ID63 and ID64 reduced Aβ, soluble alpha APP (sAPPα), and lactate levels in SH-SY5Y-APP695 cells. The latter might be explained by enhanced expression of lactate dehydrogenase (LDHA). Micronutrient combinations had no effects on mitochondrial parameters in SH-SY5Y-APP695 cells. ID64 showed a significant life-prolonging effect in C. elegans CL2006. Incubation of GMC101 with ID63 significantly lowered Aβ aggregation. Both combinations significantly reduced paralysis and thus improved the phenotype in GMC101. Thus, the combinations of the tested biofactors are effective in pre-clinical models of AD by interfering with Aβ related pathways and glycolysis.     

Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer’s Disease Patients: Clinical,Neuroimaging and Neuropathological Findings

In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer’s disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.     

基于乙酰胆碱酯酶和氧化应激研究海胆酮对阿尔茨海默症的作用机制

海胆酮是一种酮式类胡萝卜素,主要从海胆及藻类等海洋生物中提取。本文研究海胆酮对乙酰胆碱酯酶（acetylcholinesterase,AChE）的抑制作用,应用酶动力学、荧光光谱、圆二色光谱和分子对接技术研究海胆酮对AChE的抑制机理,并用淀粉样β蛋白片段25～35（amyloid beta-peptide 25-35,Aβ25-35）诱导大鼠肾上腺嗜铬细胞瘤细胞（PC12细胞）建立阿尔茨海默症（Alzheimer’s disease,AD）模型,研究海胆酮对AD细胞模型氧化应激损伤的作用。结果表明,海胆酮有很强的AChE抑制活性,其半抑制质量浓度为（16.29±0.97）μg/mL,抑制常数Ki为3.82 μg/mL,表现为竞争性抑制;海胆酮可诱导AChE二级结构改变,更容易与AChE活性中心氨基酸Ser200、His440、Trp84和Tyr121结合,阻碍底物碘代硫代乙酰胆碱（acetylthiocholine iodide,ATCI）与酶结合,从而引起酶活力降低。海胆酮能有效抑制Aβ25-35诱导PC12细胞的AChE活力,降低丙二醛含量,增加超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶活力,减轻Aβ25-35诱导的PC12细胞氧化应激损伤。本研究基于AChE和氧化应激阐明了海胆酮对AD的潜在作用机制,为海胆酮在功能食品、生物医药等领域的应用提供了数据支持和理论根据。     

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.