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Brian Murray, Bhanushee Sharma, Georges Belfort
Although the amyloid (abeta peptide, Aβ) hypothesis is 25 years old, is the dominant model of Alzheimer's disease (AD) pathogenesis, and guides the development of potential treatments, it is still controversial. One possible reason is a lack of a mechanistic path from the cleavage products of the amyloid precursor protein (APP) such as soluble Aβ monomer and soluble molecular fragments to the deleterious effects on synaptic form and function. From a review of the recent literature and our own published work including aggregation kinetics and structural morphology, Aβ clearance, molecular simulations, long-term potentiation measurements with inhibition binding, and the binding of a commercial monoclonal antibody, aducanumab, we hypothesize that the N-terminal domains of neurotoxic Aβ oligomers are implicated in causing the disease...
February 10, 2017: ACS Chemical Neuroscience
Junxia Lu, Xing-Qi Dong, Jian-Jun Zhang
Alzheimer's disease (AD) has become the most common neurodegenerative disease. The deposition of amyloid fibrils in the brain is one of the characteristics of AD. The fibrils are composed of amyloid-b peptide (Ab). Ab is produced through a series event of protease cleavage of a transmembrane protein called β-amyloid precursor protein (APP) which is commonly expressed in the brain. The production of Ab and its propensity to aggregation to form oligomers and fibrils are believed to initiate a sequence of events that lead to AD dementia...
February 8, 2017: Protein and Peptide Letters
T Harach, N Marungruang, N Duthilleul, V Cheatham, K D Mc Coy, G Frisoni, J J Neher, F Fåk, M Jucker, T Lasser, T Bolmont
Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice...
February 8, 2017: Scientific Reports
Tuancheng Feng, Prasad Tammineni, Chanchal Agrawal, Yu Young Jeong, Qian Cai
β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for amyloid-β generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation...
February 3, 2017: Journal of Biological Chemistry
Alexandre Vallée, Yves Lecarpentier
The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia...
2016: Frontiers in Neuroscience
William M Pardridge
INTRODUCTION: Therapeutic antibodies are large molecule drugs that do not cross the blood-brain barrier (BBB). Therefore, drug development of therapeutic antibodies for Alzheimer's disease (AD) requires that these molecules be re-engineered to enable BBB delivery. This is possible by joining the therapeutic antibody with a transporter antibody, resulting in the engineering of a BBB-penetrating bispecific antibody (BSA). AREAS COVERED: The manuscript covers transporter antibodies that cross the BBB via receptor-mediated transport systems on the BBB, such as the insulin receptor or transferrin receptor...
September 7, 2016: Expert Opinion on Biological Therapy
Xiaojuan Yang, Yuzhou Yuan, Qiao Niu
OBJECTIVE: To study the effect of aluminum chloride on amyloid precursor protein ( APP ) promoter methylation and the content of amyloid beta-protein (Abeta) in hippocampus of rats. METHODS: Forty male SPF grade SD rats were divided into four groups: control group (0.9% NaCl), 10 mg/kg AlCl3 group, 20 mg/kg AlCl3 group, and 30 mg/kg AlCl3 group, respectively. After treatment for 8 weeks, the APP methylation level and expressions of APP mRNA was detected by methylation specific PCR and quantitative real time PCR, respectively...
May 2016: Wei Sheng Yan Jiu, Journal of Hygiene Research
Pham Dinh Quoc Huy, Quan Van Vuong, Giovanni La Penna, Peter Faller, Mai Suan Li
The classical force field, which is compatible with the Amber force field 99SB, has been obtained for the interaction of Cu(II) with monomer and dimers of amyloid beta peptides using the coordination where Cu(II) is bound to His6, His13 (or His14) and Asp1 with distorted planar geometry. The newly developed force field and molecular dynamics simulation were employed to study the impact of Cu(II) binding on structures and dynamics of Aβ42 monomer and dimers. It was shown that in the presence of Cu(II) the beta content of monomer is reduced substantially compared to the wild type Aβ42 suggesting that, in accord with experiments, metal ions facilitate formation of amorphous aggregates rather than amyloid fibrils with cross-beta structures...
July 25, 2016: ACS Chemical Neuroscience
Cai-feng Zhu, Jian-jian Sun, Wei Han, Jun Yang
OBJECTIVE: To observe the effect of moxibustion of "Baihui" (GV 20), etc. on learning-memory ability, hip- pocampal amyloid beta (AP) protein expression and immune activity in mild cognitive impairment (MCI) rats, so as to reveal its mechanism underlying improving cognitive impairment. METHODS: A total of 48 SD rats were randomly divided into normal, model, moxibustion, and medication groups (n = 12 in each group). The MCI model was established by intraperitoneal injection of 2 mL mixture solution containing D-galactose (120 mg - kg- - d-) and Sodium Nitrite (90 mg x kg(-1) x d(-1)), once daily for 40 days...
April 2016: Zhen Ci Yan Jiu, Acupuncture Research
Mei-chi Jiang, Jing Liang, Yu-jie Zhang, Jing-rong Wang, Jin-dong Hao, Mei-kang Wang, Jian Xu
OBJECTIVE: To observe the effect of acupuncture stimulation of bilateral "Hegu" (LI 4) and "Taichong" (LR 3, the so-called "Four Gate Points") on learning-memory ability, hippocampal interleukin-1 (IL-1) P and IL-2 and amyloid beta (Abeta) 42 levels in Alzheimer's disease (AD) rats,so as to reveal its underlying mechanism in improving AD. METHODS: Male SD rats were randomly divided into sham operation, model, medication and acupuncture groups (n = 12 rats in each group)...
April 2016: Zhen Ci Yan Jiu, Acupuncture Research
Haruhiko Akiyama
The development of disease-modifying therapy (DMT) that can arrest the pathological processes of Alzheimer's disease (AD) has emerged as one of the highest priorities of medical research. Two pathological hallmarks, amyloid-beta (Abeta) protein deposition and tau accumulation, are the major targets of DMT. Immunotherapy for Abeta removal and secretase inhibitors/modulators that reduce total or accumulation-prone Abeta are candidate DMTs against Abeta. Compounds that prevent tau aggregation are also under development...
April 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
Wenjing Liu, Heng Cai, Meiqing Lin, Lu Zhu, Lili Gao, Renjia Zhong, Siwei Bi, Yixue Xue, Xiuli Shang
The disruption of blood-brain barrier (BBB) and endothelial cell dysfunction, associated with the cerebrovascular deposition of the amyloid-beta (Abeta) protein, have been characterized as the key pathological characteristics in Alzheimer's disease (AD). In various biologic processes of AD, researchers have proven that mircroRNAs (miRNAs) play critical roles. However, the role and function of miRNAs in the disruption of BBB of AD still remain unclear. Here, we found that mircroRNA-107 (miR-107) is endogenously expressed in human brain microvascular endothelial cells (ECs) of BBB model, while it is significantly down-regulated in ECs pre-incubated with Abeta...
May 1, 2016: Experimental Cell Research
Weigang Cui, Yinghua Zhang, Chenxi Yang, Yiyuan Sun, Min Zhang, Songtao Wang
Neuronal cell apoptosis is an important pathological change in Alzheimer's disease (AD). Hydrogen sulfide (H(2)S) is known to be a novel gaseous signaling molecule and a cytoprotectant in many diseases including AD. However, the molecular mechanism of the antiapoptosis activity of H(2)S in AD is not yet fully understood. The aim of the present study is to evaluate the inhibitory effects of H(2)S on Abeta (Aβ)-induced apoptosis and the molecular mechanisms underlying primary neuron cells. Our results showed that sodium hydrosulfide (NaHS), a donor of H(2)S, significantly ameliorated Aβ-induced cell apoptosis...
June 14, 2016: Neuroscience
Da-Peng Jiang, Jin-Hui Li, Jie Zhang, Sheng-Long Xu, Fang Kuang, Hai-Yang Lang, Ya-Feng Wang, Guang-Zhou An, Jing Li, Guo-Zhen Guo
A progressively expanded literature has been devoted in the past years to the noxious or beneficial effects of electromagnetic field (EMF) to Alzheimer׳s disease (AD). This study concerns the relationship between electromagnetic pulse (EMP) exposure and the occurrence of AD in rats and the underlying mechanisms, focusing on the role of oxidative stress (OS). 55 healthy male Sprague Dawley (SD) rats were used and received continuous exposure for 8 months. Morris water maze (MWM) test was conducted to test the ability of cognitive and memory...
March 10, 2016: Brain Research
Connie Marras, K Ray Chaudhuri
Parkinson's disease is highly heterogeneous in early clinical features and later outcomes. This makes classifying subgroups of PD relevant to clinical research and practice, particularly if they are prognostically relevant. Subgroups have been defined both on the basis of motor and nonmotor features, and subgroups have been determined either empirically, based on clinical observation, or using data-driven analytic techniques. Previous studies have examined both the overall number and the nature of nonmotor symptoms and signs in tremor-dominant compared with non-tremor-dominant subtypes, and longitudinal studies identify nonmotor symptoms as important markers of prognosis and important defining features of PD subtypes...
August 2016: Movement Disorders: Official Journal of the Movement Disorder Society
M A Busche, M Staufenbiel, M Willem, C Haass, H Förstl
Alzheimer's disease (AD) is characterized by the pathological accumulation of amyloid-beta (Abeta) and tau peptides in the brain. Recent evidence suggests that the soluble peptide amyloid-eta (Aeta) may have an additional role in the pathogenesis of AD. The detailed investigation of the cellular and neurophysiological mechanisms underlying AD has revealed surprising results that may become highly relevant for the early diagnosis and treatment of the disease. By analyzing the function of single neurons and large-scale networks in intact brains in vivo it has been shown that A-beta, tau and A-eta abnormally modulate brain activity and obviously unfold contrasting effects: while A-beta promotes neuronal hyperactivity as well as epileptiform activity, tau and A-eta reduce the activity of neurons...
November 2016: Der Nervenarzt
Bruno Vasconcelos, Ilie-Cosmin Stancu, Arjan Buist, Matthew Bird, Peng Wang, Alexandre Vanoosthuyse, Kristof Van Kolen, An Verheyen, Pascal Kienlen-Campard, Jean-Noël Octave, Peter Baatsen, Diederik Moechars, Ilse Dewachter
Genetic, clinical, histopathological and biomarker data strongly support Beta-amyloid (Aβ) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer's Disease (AD), while the underlying mechanism remains unclear. In vivo preclinical models have reproducibly recapitulated Aβ-induced Tau-pathology. Tau pathology was thereby also induced by aggregated Aβ, in functionally connected brain areas, reminiscent of a prion-like seeding process...
April 2016: Acta Neuropathologica
Yan Hong, Chao Shen, Qingqing Yin, Menghan Sun, Yingjuan Ma, Xueping Liu
An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-β binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated...
May 2016: Neurochemical Research
Zhenyu Yin, Tingting Yul, Yun Xu
Alzheimer's disease (AD) is the most common form of dementia which is caused by accumulation in the brain of plaques made up of amyloid beta-peptide (Abeta). Research on nanosized systems indicated that nanoparticles (NPs) could pass across the blood-brain barrier (BBB) and improve the visibility of internal body structures in magnetic resonance imaging (MRI), which made it possible to aid the early diagnosis of AD. In this research study we synthesized magnetite nanoparticles by high-temperature solution-phase reaction, transferred into water based on a ligand exchange process and coated with meso-2,3-dimercaptosuccinic (DMSA)...
September 2015: Journal of Nanoscience and Nanotechnology
Shinsaku Ito, Ken Ito, Naoko Abeta, Ryo Takahashi, Yasuyuki Sasaki, Shunsuke Yajima
Strigolactones (SLs) are a group of terpenoid lactones found in plants that regulate diverse developmental phenomena. SLs are thought to be involved in the maintenance of phosphate homeostasis. In addition, SL signaling is required for the regulation of shoot branching by nitrogen supply in Arabidopsis. In this study, we evaluated the effects of SLs on nitrogen deficient-inducing phenomena (leaf senescence and reduction of plant weight) in Arabidopsis. SL-biosynthesis (max1-1) and SL-insensitive (atd14-1) mutants showed altered responses to nitrogen deficient in comparison with wild-type (WT) plants...
2016: Plant Signaling & Behavior
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