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Tau, tau oligomers, amyloid channels

Ki Hoon Lee, Sei-Jung Lee, Hyun Jik Lee, Gee Euhn Choi, Young Hyun Jung, Dah Ihm Kim, Amr Ahmed Gabr, Jung Min Ryu, Ho Jae Han
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid β1-42 (Aβ) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aβ induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aβ with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death...
2017: Frontiers in Molecular Neuroscience
Gianluigi Forloni, Vladimiro Artuso, Pietro La Vitola, Claudia Balducci
The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides...
June 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Takayuki Ohnishi, Masako Yanazawa, Tomoya Sasahara, Yasuki Kitamura, Hidekazu Hiroaki, Yugo Fukazawa, Isao Kii, Takashi Nishiyama, Akiyoshi Kakita, Hiroyuki Takeda, Akihide Takeuchi, Yoshie Arai, Akane Ito, Hitomi Komura, Hajime Hirao, Kaori Satomura, Masafumi Inoue, Shin-ichi Muramatsu, Ko Matsui, Mari Tada, Michio Sato, Eri Saijo, Yoshiki Shigemitsu, Satoko Sakai, Yoshitaka Umetsu, Natsuko Goda, Naomi Takino, Hitoshi Takahashi, Masatoshi Hagiwara, Tatsuya Sawasaki, Genji Iwasaki, Yu Nakamura, Yo-ichi Nabeshima, David B Teplow, Minako Hoshi
Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration...
August 11, 2015: Proceedings of the National Academy of Sciences of the United States of America
Kathlyn J Gan, Michael A Silverman
Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline...
March 15, 2015: Molecular Biology of the Cell
Sangmook Lee, Jill Zemianek, Thomas B Shea
Alzheimer's disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm-5 μM) of human Aβ1-42 perturbed synaptic transmission within hours...
2013: Journal of Alzheimer's Disease: JAD
Maria Manczak, P Hemachandra Reddy
The purpose of our study was to determine the relationship between voltage-dependent anion channel 1 protein (VDAC1) and amyloid beta (Aβ) and phosphorylated tau in Alzheimer's disease (AD). Using brain specimens from AD patients, control subjects and 6-, 12- and 24-month-old Aβ precursor protein (APP) transgenic mice, we studied VDAC1 protein levels. Further, we also studied the interaction between VDAC1 and Aβ (monomers and oligomers) and phosphorylated tau, using cortical issues from AD patients, control subjects, APP, APP/PS1 and 3XTg...
December 1, 2012: Human Molecular Genetics
Evangelyn Dominguez, Ting-Yu Chin, Chih-Ping Chen, Tzong-Yuan Wu
Alzheimer's disease (AD) is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs...
December 2011: Taiwanese Journal of Obstetrics & Gynecology
Thimmappa S Anekonda, Joseph F Quinn
Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex...
December 2011: Biochimica et Biophysica Acta
Kenji Yamamoto, Yoshifumi Ueta, Li Wang, Ryo Yamamoto, Naoko Inoue, Kaoru Inokuchi, Atsu Aiba, Hideto Yonekura, Nobuo Kato
It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons...
August 3, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dong Liu, Michael Pitta, Jong-Hwan Lee, Balmiki Ray, Debomoy K Lahiri, Katsutoshi Furukawa, Mohamed Mughal, Haiyang Jiang, Julissa Villarreal, Roy G Cutler, Nigel H Greig, Mark P Mattson
Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD...
2010: Journal of Alzheimer's Disease: JAD
Leslie Crews, Eliezer Masliah
Alzheimer's disease (AD) is characterized by cognitive impairment, progressive neurodegeneration and formation of amyloid-beta (Abeta)-containing plaques and neurofibrillary tangles composed of hyperphosphorylated tau. The neurodegenerative process in AD is initially characterized by synaptic damage accompanied by neuronal loss. In addition, recent evidence suggests that alterations in adult neurogenesis in the hippocampus might play a role. Synaptic loss is one of the strongest correlates to the cognitive impairment in patients with AD...
April 15, 2010: Human Molecular Genetics
E Zerovnik
The whole set of so-called >conformational< disorders, among them systemic amyloidoses, various dementias and other neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotropic lateral sclerosis, may have similar molecular backgrounds: changes in protein conformation and aggregation lead to toxic amyloid oligomers and fibrils. The so called aggresomes in eukaryotes (equivalent to inclusion bodies in prokaryotes), located at the centriole by the nucleus and composed of aggregated proteins, are believed to sequester the toxic material...
February 2010: Current Alzheimer Research
Rosa Resende, Elisabete Ferreiro, Cláudia Pereira, Catarina Resende Oliveira
Intracellular neurofibrillary tangles, one of the characteristic hallmarks of Alzheimer's disease (AD), are mainly composed of hyperphosphorylated tau. The abnormal tau phosphorylation seems to be related to altered activity of kinases such as glycogen synthase kinase-3beta (GSK-3beta). Tau pathology is thought to be a later event during the progression of the disease, and it seems to occur as a consequence of amyloid-beta (Abeta) peptide accumulation. The aim of this work was to investigate whether soluble Abeta1-42, particularly oligomers that correspond to the neurotoxic species involved early in the development of AD, triggers tau phosphorylation by a mechanism involving activation of tau-kinase GSK-3beta...
July 2008: Journal of Neuroscience Research
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