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https://www.readbyqxmd.com/read/28432017/dual-functional-nanoparticles-for-precise-drug-delivery-to-alzheimer-s-disease-lesions-targeting-mechanisms-pharmacodynamics-and-safety
#1
Xiaoyao Zheng, Chi Zhang, Qian Guo, Xu Wan, Xiayan Shao, Qingfeng Liu, Qizhi Zhang
Alzheimer's disease (AD) is the most common form of dementia and is characterized by the cerebral accumulation of extracellular amyloid plaques. In a previous study, this histopathological hallmark was used as a target on a dual-functional nanoparticle (TQNP) to deliver biotechnological drugs, such as the H102 peptide, a β-sheet breaker, to AD lesions precisely. This delivery system could reduce the amyloid-β (Aβ) burden in the brains of AD model mice, as well as ameliorated the memory impairment of the mice...
April 18, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28431929/effects-of-naturally-occurring-charged-mutations-on-the-structure-stability-and-binding-of-the-pin1-ww-domain
#2
Xiaoya Qiao, Ying Liu, Liting Luo, Lei Chen, Caixian Zhao, Xuanjun Ai
Pin1 is a peptidyl-prolyl cis-trans isomerase, whose WW domain specifically recognizes the pSer/Thr-Pro motif. Pin1 is involved in multiple phosphorylation events that regulate the activities of various substrates, and Pin1 deregulation has been reported in various diseases, including cancer and Alzheimer's disease. The WW domain of Pin1 has been used as a small model protein to investigate the folding mechanisms of the β-sheet structure by studying the effect of mutations or its naturally occurring variants...
April 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28427866/effect-of-amyloid-%C3%AE-25-35-in-hyperglycemic-and-hyperinsulinemic-rats-effects-on-phosphorylation-and-o-glcnacylation-of-tau-protein
#3
Liliana Lozano, Jorge Guevara, Tony Lefebvre, Ivan Ramos-Martinez, Daniel Limón, Alfonso Díaz, Eduarda Cerón, Edgar Zenteno
Aggregation of the amyloid beta (Aβ) peptide and hyperphosphorylation of tau protein, which are markers of Alzheimer's disease (AD), have been reported also in diabetes mellitus (DM). One regulator of tau phosphorylation is O-GlcNAcylation, whereas for hyperphosphorylation it could be GSK3beta, which is activated in hyperglycemic conditions. With this in mind, both O-GlcNAcylation and phosphorylation of tau protein were evaluated in the brain of rats with streptozotocin (STZ)-induced hyperglycemia and hyperinsulinemia and treated with the Aß25-35 peptide in the hippocampal region CA1...
April 6, 2017: Neuropeptides
https://www.readbyqxmd.com/read/28424976/the-involvement-of-nr2b-and-tau-protein-in-mg132-induced-creb-dephosphorylation
#4
Min Xie, Yuan Li, Shao-Hui Wang, Qun-Tao Yu, Xin Meng, Xiao-Mei Liao
Transcription factor cAMP response element-binding protein (CREB) plays a critical role in memory formation. Ubiquitin-proteasome system-dependent protein degradation affects the upstream signaling pathways which regulate CREB activity. However, the molecular mechanisms of proteasome inhibition on reductive CREB activity are still unclear. The current study demonstrated that MG132-inhibited proteasome activity resulted in a dose dependence of CREB dephosphorylation at Ser133 as well as decreased phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunit NR2B (Tyr1472) and its tyrosine protein kinase Fyn (Tyr416)...
April 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28422052/folic-acid-reduces-tau-phosphorylation-by-regulating-pp2a-methylation-in-streptozotocin-induced-diabetic-mice
#5
Miaoyan Zheng, Chen Zou, Mengyue Li, Guowei Huang, Yuxia Gao, Huan Liu
High incidence rate of Alzheimer's disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice...
April 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28420443/tau-phosphorylation-induced-by-severe-closed-head-traumatic-brain-injury-is-linked-to-the-cellular-prion-protein
#6
Richard Rubenstein, Binggong Chang, Natalia Grinkina, Eleanor Drummond, Peter Davies, Meir Ruditzky, Deep Sharma, Kevin Wang, Thomas Wisniewski
Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-β oligomers (Aβo). This PrP(C)-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Aβo production but upstream of intracellular toxicity within neurons...
April 18, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28416463/glucocorticoids-activate-a-synapse-weakening-pathway-culminating-in-tau-phosphorylation-in-the-hippocampus
#7
Jee Hyun Yi, Christopher Brown, Garry Whitehead, Thomas Piers, Young Seok Lee, Celia Martinez Perez, Philip Regan, Daniel J Whitcomb, Kwangwook Cho
Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function...
April 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28416393/tdp-43-expression-influences-amyloid%C3%AE-plaque-deposition-and-tau-aggregation
#8
Stephani A Davis, Kok Ann Gan, James A Dowell, Nigel J Cairns, Michael A Gitcho
Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9)...
April 14, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28413987/alzheimer-s-disease-like-early-phase-brain-pathogenesis-self-curing-amelioration-of-neurodegeneration-from-pro-inflammatory-wounding-to-anti-inflammatory-healing
#9
Jiang He, Tao Liao, Guo-Xin Zhong, Ji-Da Zhang, Yan-Ping Chen, Qi Wang, Qing-Ping Zeng
The etiological initiators of neuroinflammation remain inclusive, and effective interventions to block neurodegeneration are unavailable. Surprisingly, we found collagen II-combined complete Freund's adjuvant (CC) that usually induces rheumatoid arthritis (RA) also drives Alzheimer's disease (AD)-like neurodegeneration in mice. CC not only upregulates the cerebral pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8), but also downregulates the cerebral interleukin 10 (IL-10), an anti-inflammatory cytokine, and tyrosine hydroxylase (TH), a rate-limiting enzyme for biosynthesis of the anti-inflammatory neurotransmitter dopamine...
April 17, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28413833/beneficial-effects-of-a-pyrroloquinolinequinone-containing-dietary-formulation-on-motor-deficiency-cognitive-decline-and-mitochondrial-dysfunction-in-a-mouse-model-of-alzheimer-s-disease
#10
Darrell Sawmiller, Song Li, Takashi Mori, Ahsan Habib, David Rongo, Vedad Delic, Patrick C Bradshaw, R Douglas Shytle, Cyndy Sanberg, Paula Bickford, Jun Tan
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP) proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT). A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II), containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation) and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis) in 5XFAD transgenic mice...
April 2017: Heliyon
https://www.readbyqxmd.com/read/28412305/memantine-improves-outcomes-after-repetitive-traumatic-brain-injury
#11
Zhengrong Mei, Jianhua Qiu, Sasha Alcon, Jumana Hashim, Alexander Rotenberg, Yan Sun, William P Meehan, Rebekah Mannix
Repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions) is common and results in significant cognitive impairment. Targeted therapies for rmTBI are lacking, though evidence from other injury models indicates that targeting N-methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated glutamatergic toxicity might mitigate rmTBI-induced neurologic deficits. However, there is a paucity of preclinical or clinical data regarding NMDAR antagonist efficacy in the rmTBI setting. To test whether NMDAR antagonist therapy improves outcomes after rmTBI, mice were subjected to rmTBI injury (4 injuries in 4 days) and randomized to treatment with the NMDA antagonist memantine or with vehicle...
April 12, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28412141/toll-like-receptor-4-activation-can-be-either-detrimental-or-beneficial-following-mild-repetitive-traumatic-brain-injury-depending-on-timing-of-activation
#12
Frances Corrigan, Alina Arulsamy, Lyndsey E Collins-Praino, Joshua L Holmes, Robert Vink
A history of repeated concussion has been linked to the later development of neurodegeneration, which is associated with the accumulation of hyperphosphorylated tau and the development of behavioral deficits. However, the role that exogenous factors, such as immune activation, may play in the development of neurodegeneration following repeated mild traumatic brain injury (rmTBI) has not yet been explored. To investigate, male Sprague-Dawley rats were administered three mTBIs 5 days apart using the diffuse impact-acceleration model to generate ∼100G...
April 13, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28408165/alterations-in-protein-phosphorylation-in-the-amygdala-of-the-5xfamilial-alzheimer-s-disease-animal-model
#13
Eun-Jeong Yang, Usman Mahmood, Hyunju Kim, Moonseok Choi, Yunjung Choi, Jean-Pyo Lee, Moon-Jeong Chang, Hye-Sun Kim
Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy...
March 31, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28408124/tau-antibody-targeting-pathological-species-block-neuronal-uptake-and-interneuron-propagation-of-tau-in%C3%A2-vitro
#14
Chloe K Nobuhara, Sarah L DeVos, Caitlin Commins, Susanne Wegmann, Benjamin D Moore, Allyson D Roe, Isabel Costantino, Matthew P Frosch, Rose Pitstick, George A Carlson, Christoph Hock, Roger M Nitsch, Fabio Montrasio, Jan Grimm, Anne E Cheung, Anthone W Dunah, Marion Wittmann, Thierry Bussiere, Paul H Weinreb, Bradley T Hyman, Shuko Takeda
The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy...
April 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28405187/identification-of-cerebral-metal-ion-imbalance-in-the-brain-of-aging-octodon-degus
#15
Nady Braidy, Anne Poljak, Chris Marjo, Helen Rutlidge, Anne Rich, Bat-Erdene Jugder, Tharusha Jayasena, Nibaldo C Inestrosa, Perminder S Sachdev
The accumulation of redox-active transition metals in the brain and metal dyshomeostasis are thought to be associated with the etiology and pathogenesis of several neurodegenerative diseases, and Alzheimer's disease (AD) in particular. As well, distinct biometal imaging and role of metal uptake transporters are central to understanding AD pathogenesis and aging but remain elusive, due inappropriate detection methods. We therefore hypothesized that Octodon degus develop neuropathological abnormalities in the distribution of redox active biometals, and this effect may be due to alterations in the expression of lysosomal protein, major Fe/Cu transporters, and selected Zn transporters (ZnTs and ZIPs)...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28404803/neuropsychiatric-symptoms-predict-hypometabolism-in-preclinical-alzheimer-disease
#16
Kok Pin Ng, Tharick A Pascoal, Sulantha Mathotaarachchi, Chang-Oh Chung, Andréa L Benedet, Monica Shin, Min Su Kang, Xiaofeng Li, Maowen Ba, Nagaendran Kandiah, Pedro Rosa-Neto, Serge Gauthier
OBJECTIVE: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). METHODS: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [(18)F]florbetapir PET and CSF phosphorylated tau biomarkers...
April 12, 2017: Neurology
https://www.readbyqxmd.com/read/28402338/insulin-deprivation-induces-pp2a-inhibition-and-tau-hyperphosphorylation-in-htau-mice-a-model-of-alzheimer-s-disease-like-tau-pathology
#17
Maud Gratuze, Jacinthe Julien, Franck R Petry, Françoise Morin, Emmanuel Planel
Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28400815/delayed-treatment-of-secondary-degeneration-following-acute-optic-nerve-transection-using-a-combination-of-ion-channel-inhibitors
#18
Nathanael J Yates, Marcus K Giacci, Ryan L O'Hare Doig, Wissam Chiha, Bethany E Ashworth, Jade Kenna, Carole A Bartlett, Melinda Fitzgerald
Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca(2+) entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO(@) pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery...
February 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28400814/neuroprotective-effect-of-the-chinese-medicine-tiantai-no-1-and-its-molecular-mechanism-in-the-senescence-accelerated-mouse-prone-8
#19
Ying-Hong Li, Xu-Sheng Wang, Xiao-Lin Chen, Yu Jin, Hong-Bo Chen, Xiu-Qin Jia, Yong-Feng Zhang, Zheng-Zhi Wu
Tiantai No. 1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2:1:2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No. 1 intragastrically to senescence-accelerated mouse prone 8 (SAMP8) mice (a model of Alzheimer's disease) at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer's disease-related proteins in the brain...
February 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28400135/insulin-deficiency-results-in-reversible-protein-kinase-a-activation-and-tau-phosphorylation
#20
Judith M van der Harg, Leslie Eggels, Fabian N Bangel, Silvie R Ruigrok, Rob Zwart, Jeroen J M Hoozemans, Susanne E la Fleur, Wiep Scheper
Alzheimer's disease (AD) is a highly prevalent multifactorial disease for which Diabetes Mellitus (DM) is a risk factor. Abnormal phosphorylation and aggregation of tau is a key hallmark of AD. In animal models, DM induces or exacerbates the phosphorylation of tau, suggesting that DM may influence the risk at AD by directly facilitating tau pathology. Previously we reported that tau phosphorylation induced in response to metabolic stress is reversible. Since identification and understanding of early players in tau pathology is pivotal for therapeutic intervention, we here investigated the mechanism underlying tau phosphorylation in the diabetic brain and its potential for reversibility...
April 8, 2017: Neurobiology of Disease
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