The molecular genetics of Alzheimer's disease

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of β-amyloid peptide (Aβ) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for β-amyloid precursor protein (βAPP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the βAPP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the βAPP mutations cause the disease and discuss recent advances in βAPP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of theAPOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of βAPP and its derivatives.     

运动与阿尔茨海默病：基于Tau蛋白翻译后修饰视角的研究述评

阿尔茨海默病（Alzheimer’s disease,AD）是一种与年龄有关的神经退行性疾病,严重危害老年人的身心健康,给社会带来巨大的经济压力。但目前其发病机制尚不完全明确,临床仍无根治的有效方法。Tau蛋白是一种微管相关蛋白质,能够参与维持微管相关结构稳定,具有可溶性且不会聚集。在AD病理状态下,病人脑内Tau蛋白结构和功能异常。异常的Tau蛋白聚集成不可溶的神经纤维缠结,损害微管运输能力,导致病人认知功能障碍。Tau蛋白结构和功能的改变是由多种翻译后修饰过程来调控的,即将特定的化学修饰基团与Tau蛋白N-端或C-端结合,直接改变蛋白质的性质和功能。AD病人脑内Tau蛋白的磷酸化、糖基化、乙酰化及SUMO化等多种翻译后修饰异常,与Tau蛋白的降解和毒性物质的聚集密切相关。本文综述近年来的研究后发现,运动可以通过改善Tau蛋白翻译后的某些异常修饰来预防和改善AD,主要作用方式如下：(1）运动可通过抑制GSK 3β和MAPK等蛋白激酶活性来抑制Tau蛋白的过度磷酸化,可能通过上调PP2A活性来促进Tau蛋白去磷酸化;(2）运动可通过提高GLUT1和GLUT3蛋白质水平,可能通过调节OGA和OGT活性平衡,提高蛋白质O-GlcNAc糖基化水平;(3）运动可能通过AMPK/mTORC1途径抑制p300以及激活SIRT1,降低Tau蛋白乙酰化水平;同时运动还可能通过抑制HDAC6,改善Tau蛋白KXGS基序异常乙酰化程度;(4）运动可能通过调节磷酸化与SUMO化共定位点,改善Tau蛋白异常SUMO化水平。     

Deep Convolution Neural Network Based System for Early Diagnosis of Alzheimer's Disease

ObjectivesAlzheimer's Disease (AD) is the most general type of dementia. In all leading countries, it is one of the primary reasons of death in senior citizens. Currently, it is diagnosed by calculating the MSME score and by the manual study of MRI Scan. Also, different machine learning methods are utilized for automatic diagnosis but existing has some limitations in terms of accuracy. So, main objective of this paper to include a preprocessing method before CNN model to increase the accuracy of classification.Materials and methodIn this paper, we present a deep learning-based approach for detection of Alzheimer's Disease from ADNI database of Alzheimer's disease patients, the dataset contains fMRI and PET images of Alzheimer's patients along with normal person's image. We have applied 3D to 2D conversion and resizing of images before applying VGG-16 architecture of Convolution neural network for feature extraction. Finally, for classification SVM, Linear Discriminate, K means clustering, and Decision tree classifiers are used.ResultsThe experimental result shows that the average accuracy of 99.95% is achieved for the classification of the fMRI dataset, while the average accuracy of 73.46% is achieved with the PET dataset. On comparing results on the basis of accuracy, specificity, sensitivity and on some other parameters we found that these results are better than existing methods.Conclusionsthis paper, suggested a unique way to increase the performance of CNN models by applying some preprocessing on image dataset before sending to CNN architecture for feature extraction. We applied this method on ADNI database and on comparing the accuracies with other similar approaches it shows better results.     

Surface-bound basement membrane components accelerate amyloid-β peptide nucleation in air-free wells: An in vitro model of cerebral amyloid angiopathy

Cerebral amyloid angiopathy is caused by deposition of the amyloid β-peptide which consists of mainly 39–40 residues to the cortical and leptomeningeal vessel walls. There are no definite in vitro systems to support the hypothesis that the vascular basement membrane may act as a scaffold of amyloid β-peptide carried by perivascular drainage flow and accelerate its amyloid fibril formation in vivo. We previously reported the critical roles of interfaces and agitation on the nucleation of amyloid fibrils at low concentrations of amyloid β-peptide monomers. Here, we reproduced the perivascular drainage flow in vitro by using N-hydroxysuccinimide-Sepharose 4 Fast flow beads as an inert stirrer in air-free wells rotated at 1 rpm. We then reproduced the basement membranes in the media of cerebral arteries in vitro by conjugating Matrigel and other proteins on the surface of Sepharose beads. These beads were incubated with 5 μM amyloid β(1–40) at 37 °C without air, where amyloid β(1–40) alone does not form amyloid fibrils. Using the initiation time of fibril growth kinetics (i.e., the lag time of fibril growth during which nuclei, on-pathway oligomers and protofibrils are successively formed) as a parameter of the efficiency of biological molecules to induce amyloid fibril formation, we found that basement membrane components including Matrigel, laminin, fibronectin, collagen type IV and fibrinogen accelerate the initiation of amyloid β-peptide fibril growth in vitro. These data support the essential role of vascular basement membranes in the development of cerebral amyloid angiopathy.     

天蚕素AD在毕赤酵母中的多拷贝整合表达及表达条件优化

【背景】天蚕素抗菌肽是目前研究最清楚、效果最显著的抗菌肽,实现工业化生产为其在农业、养殖业中的应用奠定了基础。【目的】获得一株高效生产天蚕素AD的基因工程菌株。【方法】构建重组载体pGAPZαA-CAD通过电击转化至PichiapastorisX33中,表达天蚕素AD基因并获得X33/GCAD菌株;构建重组载体pUCGAP-CAD导入至X33/GCAD菌株中。pGAPZαA-CAD是以博来霉素为抗性筛选标签被整合到P. pastoris X33的GAPDH启动子区域,pUCGAP-CAD是以遗传霉素为抗性筛选标签被整合到P. pastoris X33的非翻译rDNA区域,最终获得一株高效表达天蚕素AD的酵母菌株X33/GUCAD。【结果】通过质谱分析鉴定X33/GUCAD表达的抑菌物质为天蚕素AD,通过发酵条件的优化,表明X33/GUCAD菌株在以甘油为碳源和以蛋白胨、酵母提取物为有机氮源的情况下具有较强表达天蚕素AD的能力。【结论】较高的拷贝数更有利于提高天蚕素AD的产量,此工程菌株在后期发酵过程中稳定性较好,适于工业化生产。     

Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case–control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel–Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR = 1.212 for T allele, 95% CI = 1.097–1.340, p-value = 0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR = 1.187 for T allele, 95% CI = 1.058–1.332, p-value = 0.004) and Asian samples (allelic model, pooled OR = 1.293 for T allele, 95% CI = 1.058–1.580, p-value = 0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value = 0.0149) and CHB (Chinese, p-value = 0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD.     

Cyclooxygenase‐1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease

Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β‐amyloid (Aβ) production and inhibit neuroinflammation. However, follow‐up clinical trials, mostly using selective cyclooxygenase (COX)‐2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX‐1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro‐inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX‐1 inhibition, rather than COX‐2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20‐month‐old triple transgenic AD (3 × Tg‐AD) mice with the COX‐1 selective inhibitor SC‐560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC‐560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg‐AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX‐1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg‐AD mice. Thus, selective COX‐1 inhibition should be further investigated as a potential therapeutic approach for AD.     

Protective effects of EphB2 on Aβ1–42 oligomer-induced neurotoxicity and synaptic NMDA receptor signaling in hippocampal neurons

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by the abnormal deposition of extracellular amyloid-β (Aβ) oligomers. However, the nature and precise mechanism of the toxicity of Aβ oligomers are not clearly understood. Aβ oligomers have been previously shown to cause a major loss of EphB2, a member of the EphB family of receptor tyrosine kinases. To determine the effect of EphB2 on Aβ oligomer-induced neurotoxicity and the underlying molecular mechanisms, we examined the EphB2 gene in cultured hippocampal neurons. Using a cellular model of AD, Aβ_1–42 oligomers were confirmed to induce neurotoxicity in a time-dependent manner and result in a major decrease of EphB2. EphB2 overexpression could prevent the neurotoxicity of hippocampal neurons from exposure to Aβ_1–42 oligomers for 1 h. Further analysis revealed that EphB2 overexpression increased synaptic NR1 and NR2B expression in Aβ_1–42 oligomer-treated neurons. Moreover, EphB2 overexpression prevented Aβ_1–42 oligomer-induced downregulation of dephosphorylated p38 MAPK and phosphorylated CREB. Together, these results suggest that EphB2 is a factor which protects hippocampal neurons against the toxicity of Aβ_1–42 oligomers, and we infer that the protection of EphB2 is achieved by increasing the synaptic NMDA receptor level and downstream p38 MAPK and CREB signaling in hippocampal neurons. This study provides new molecular insights into the neuroprotective effect of EphB2 and highlights its potential therapeutic role in the management of AD.