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https://www.readbyqxmd.com/read/28699522/targeting-human-astrocytes-calcium-sensing-receptors-for-treatment-of-alzheimer-s-disease
#1
Anna Chiarini, Ubaldo Armato, James F Whitfield, Ilaria Dal Pra
Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28617802/oxidative-stress-affects-processing-of-amyloid-precursor-protein-in-vascular-endothelial-cells
#2
Abebe Muche, Thomas Arendt, Reinhard Schliebs
BACKGROUND: Oxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer's disease (AD). It has been assumed that oxidative stress contributes to the ß-amyloid deposition in cerebral blood vessels. METHODS: In order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice...
2017: PloS One
https://www.readbyqxmd.com/read/28612181/low-density-lipoprotein-receptor-related-protein-1-lrp1-c4408r-mutant-promotes-amyloid-precursor-protein-app-%C3%AE-cleavage-in-vitro
#3
Huayan Hou, Ahsan Habib, Dan Zi, Kathy Tian, Jun Tian, Brian Giunta, Darrell Sawmiller, Jun Tan
Previous studies have demonstrated that the low-density lipoprotein receptor-related protein-1 (LRP1) plays conflicting roles in Alzheimer's disease (AD) pathogenesis, clearing β-amyloid (Aβ) from the brain while also enhancing APP endocytosis and resultant amyloidogenic processing. We have recently discovered that co-expression of mutant LRP1 C-terminal domain (LRP1-CT C4408R) with Swedish mutant amyloid precursor protein (APPswe) in Chinese hamster ovary (CHO) cells decreases Aβ production, while also increasing sAPPα and APP α-C-terminal fragment (α-CTF), compared with CHO cells expressing APPswe alone...
June 13, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28603494/yxqn-reduces-alzheimer-s-disease-like-pathology-and-cognitive-decline-in-appsweps1de9-transgenic-mice
#4
Xiaowan Wang, Runmin Song, Wenliang Lu, Ziyu Liu, Lichun Wang, Xiaojuan Zhu, Yanjun Liu, Zijie Sun, Jiang Li, Xiaomeng Li
Alzheimer's disease (AD) is the world's most common form of dementia, in which aggregation of amyloid-β (Aβ) is the hallmark. Unfortunately, few medicines have succeeded to completely cure AD. Yangxue Qingnao (YXQN) is a Chinese traditional medicine, and its pharmacological effect is improving cerebral blood flow. In this study, we firstly demonstrated that YXQN reduced AD-like pathology and cognitive impairment in APPswePS1dE9 (APP/PS1) mice with 2 months administration. Our data showed that YXQN substantially ameliorated behavioral defects in 10-month old APP/PS1 mice using Morris Water Maze and Y-maze tests, in which the cognitive ability of YXQN high-dose group approaches to wild type mice...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28495373/amyloid-beta-neurotoxicity-and-clearance-are-both-regulated-by-glial-group-ii-metabotropic-glutamate-receptors
#5
Daniela Durand, Lila Carniglia, Juan Turati, Delia Ramírez, Julieta Saba, Carla Caruso, Mercedes Lasaga
Astrocytes are now fully endorsed as key players in CNS functionality and plasticity. We recently showed that metabotropic glutamate receptor 3 (mGlu3R) activation by LY379268 promotes non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes, leading to increased release of neuroprotective sAPPα. Furthermore, mGlu3R expression is reduced in hippocampal astrocytes from PDAPP-J20 mice, suggesting a role for these receptors in Alzheimer's disease. The present study enquires into the role of astroglial-derived neurotrophins induced by mGlu3R activation in neurotoxicity triggered by amyloid β (Aβ)...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28464981/amyloid-precursor-protein-reduction-enhances-the-formation-of-neurofibrillary-tangles-in-a-mutant-tau-transgenic-mouse-model
#6
Virginie Vanden Dries, Virginie Stygelbout, Nathalie Pierrot, Zehra Yilmaz, Valérie Suain, Robert De Decker, Luc Buée, Jean-Noël Octave, Jean-Pierre Brion, Karelle Leroy
Alzheimer's disease is characterized by the presence of 2 neuropathological lesions: neurofibrillary tangles, composed of tau proteins which are highly phosphorylated and phosphorylated on uncommon sites, and amyloid plaques, containing the Aß peptides generated from the amyloid precursor protein (APP). Reduction of some APP proteolytic derivatives in Alzheimer's disease such as sAPPα fragment has been reported and sAPPα has been shown to affect tau phosphorylation. To investigate in vivo the effect of absence of APP protein and its fragments on tau phosphorylation and the formation of neurofibrillary tangles, we have generated mice deleted for APP gene and overexpressing a human mutant tau protein and developing neurofibrillary tangles (APPKOTg30 mice)...
April 5, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28457944/effects-of-phenothiazine-structured-compounds-on-app-processing-in-alzheimer-s-disease-cellular-model
#7
Melike Yuksel, Kevser Biberoglu, Seda Onder, K Gonca Akbulut, Ozden Tacal
The excess accumulation of amyloid-β (Aβ) peptides derived from the sequential cleavage of amyloid precursor protein (APP) by secretases, is one of the toxic key events leading to neuronal loss in Alzheimer's disease (AD). Studies have shown that cholinergic activity may also be involved in the regulation of APP metabolism. In the current study, we have investigated the roles of toluidine blue O (TBO) and thionine (TH), newly recognized phenothiazine-derived cholinesterase inhibitors, on the metabolism of APP in Chinese hamster ovary cells stably expressing human APP751 and presenilin 1 (PS70 cells)...
April 27, 2017: Biochimie
https://www.readbyqxmd.com/read/28455519/calcium-sensing-receptor-antagonist-nps-2143-restores-amyloid-precursor-protein-physiological-non-amyloidogenic-processing-in-a%C3%AE-exposed-adult-human-astrocytes
#8
Anna Chiarini, Ubaldo Armato, Daisong Liu, Ilaria Dal Prà
Physiological non-amyloidogenic processing (NAP) of amyloid precursor holoprotein (hAPP) by α-secretases (e.g., ADAM10) extracellularly sheds neurotrophic/neuroprotective soluble (s)APPα and precludes amyloid-β peptides (Aβs) production via β-secretase amyloidogenic processing (AP). Evidence exists that Aβs interact with calcium-sensing receptors (CaSRs) in human astrocytes and neurons, driving the overrelease of toxic Aβ42/Aβ42-os (oligomers), which is completely blocked by CaSR antagonist (calcilytic) NPS 2143...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429536/%C3%AE-mangostin-decreases-%C3%AE-amyloid-peptides-production-via-modulation-of-amyloidogenic-pathway
#9
Lan-Xue Zhao, Yan Wang, Ting Liu, Yan-Xia Wang, Hong-Zhuan Chen, Jian-Rong Xu, Yu Qiu
AIMS: β-amyloid (Aβ) aggregation and deposition play a central role in the pathogenic process of Alzheimer's disease (AD). α-Mangostin (α-M), a polyphenolic xanthone, have been shown to dissociate Aβ oligomers. In this study, we further investigated the effect of α-M on Aβ production and its molecular mechanism. METHODS: The Aβ and soluble amyloid precursor protein α (sAPPα) in culture medium of cortical neurons were measured by ELISA. The activities of α-, β-, and γ-secretases were assayed, and the interaction between α-M and β- or γ-secretases was simulated by molecular docking...
June 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28323038/monocular-denervation-of-visual-nuclei-modulates-app-processing-and-sapp%C3%AE-production-a-possible-role-on-neural-plasticity
#10
Juliana Ferreira Vasques, Pedro Vinícius Bastos Heringer, Renata Guedes de Jesus Gonçalves, Paula Campello-Costa, Claudio Alberto Serfaty, Adriana da Cunha Faria-Melibeu
Amyloid precursor protein (APP) is essential to physiological processes such as synapse formation and neural plasticity. Sequential proteolysis of APP by beta- and gamma-secretases generates amyloid-beta peptide (Aβ), the main component of senile plaques in Alzheimer Disease. Alternative APP cleavage by alpha-secretase occurs within Aβ domain, releasing soluble α-APP (sAPPα), a neurotrophic fragment. Among other functions, sAPPα is important to synaptogenesis, neural survival and axonal growth. APP and sAPPα levels are increased in models of neuroplasticity, which suggests an important role for APP and its metabolites, especially sAPPα, in the rearranging brain...
August 2017: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/28283595/astroglial-activation-and-altered-amyloid-metabolism-in-human-repetitive-concussion
#11
MULTICENTER STUDY
Pashtun Shahim, Yelverton Tegner, Niklas Marklund, Kina Höglund, Erik Portelius, David L Brody, Kaj Blennow, Henrik Zetterberg
OBJECTIVE: To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood-brain barrier (BBB) impairment. METHODS: A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25-12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ)...
April 11, 2017: Neurology
https://www.readbyqxmd.com/read/28212403/cerebrospinal-fluid-biomarkers-of-infantile-congenital-hydrocephalus
#12
David D Limbrick, Brandon Baksh, Clinton D Morgan, Gakwaya Habiyaremye, James P McAllister, Terrie E Inder, Deanna Mercer, David M Holtzman, Jennifer Strahle, Michael J Wallendorf, Diego M Morales
INTRODUCTION: Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value...
2017: PloS One
https://www.readbyqxmd.com/read/28209190/the-effects-of-different-familial-alzheimer-s-disease-mutations-on-app-processing-in-vivo
#13
Steinunn Thordardottir, Anne Kinhult Ståhlbom, Ove Almkvist, Håkan Thonberg, Maria Eriksdotter, Henrik Zetterberg, Kaj Blennow, Caroline Graff
BACKGROUND: Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer's disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. METHODS: In the current cross-sectional study, products of APP processing (e...
February 16, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28197076/structure-and-synaptic-function-of-metal-binding-to-the-amyloid-precursor-protein-and-its-proteolytic-fragments
#14
REVIEW
Klemens Wild, Alexander August, Claus U Pietrzik, Stefan Kins
Alzheimer's disease (AD) is ultimately linked to the amyloid precursor protein (APP). However, current research reveals an important synaptic function of APP and APP-like proteins (APLP1 and 2). In this context various neurotrophic and neuroprotective functions have been reported for the APP proteolytic fragments sAPPα, sAPPβ and the monomeric amyloid-beta peptide (Aβ). APP is a metalloprotein and binds copper and zinc ions. Synaptic activity correlates with a release of these ions into the synaptic cleft and dysregulation of their homeostasis is linked to different neurodegenerative diseases...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28197070/role-of-app-interactions-with-heterotrimeric-g-proteins-physiological-functions-and-pathological-consequences
#15
REVIEW
Philip F Copenhaver, Donat Kögel
Following the discovery that the amyloid precursor protein (APP) is the source of β-amyloid peptides (Aβ) that accumulate in Alzheimer's disease (AD), structural analyses suggested that the holoprotein resembles a transmembrane receptor. Initial studies using reconstituted membranes demonstrated that APP can directly interact with the heterotrimeric G protein Gαo (but not other G proteins) via an evolutionarily G protein-binding motif in its cytoplasmic domain. Subsequent investigations in cell culture showed that antibodies against the extracellular domain of APP could stimulate Gαo activity, presumably mimicking endogenous APP ligands...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28107420/the-polyherbal-wattana-formula-displays-anti-amyloidogenic-properties-by-increasing-%C3%AE-secretase-activities
#16
Htut Htut Htoo, Suveerawan Limsuvan, Onusa Thamsermsang, Jean-François Hernandez, Frédéric Checler, Piyarat Govitrapong, Narawut Pakaprot, Pravit Akarasereenont, Bruno Vincent
Alzheimer's disease is characterized by the deposition of insoluble amyloid-β peptides produced from the β-amyloid precursor protein (βAPP). Because α-secretase cleavage by ADAM10 and ADAM17 takes place in the middle of Aβ, its activation is considered as a promising anti-AD therapeutic track. Here we establish that the polyherbal Wattana formula (WNF) stimulates sAPPα production in cells of neuronal and non-neuronal origins through an increase of both ADAM10 and ADAM17 catalytic activities with no modification of BACE1 activity and expression...
2017: PloS One
https://www.readbyqxmd.com/read/28079060/intranasal-lactoferrin-enhances-%C3%AE-secretase-dependent-amyloid-precursor-protein-processing-via-the-erk1-2-creb-and-hif-1%C3%AE-pathways-in-an-alzheimer-s-disease-mouse-model
#17
Chuang Guo, Zhao-Hui Yang, Shuai Zhang, Rui Chai, Han Xue, Yan-Hui Zhang, Jia-Yi Li, Zhan-You Wang
Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as a neuroprotective agent. These properties make Lf a valuable therapeutic candidate for the treatment of Alzheimer's disease (AD). However, the mechanisms regulating the physiological roles of Lf in the pathologic condition of AD remain unknown. In the present study, an APPswe/PS1DE9 transgenic mouse model of AD was used. We explored whether intranasal human Lf (hLf) administration could reduce β-amyloid (Aβ) deposition and ameliorate cognitive decline in this AD model...
April 26, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28034780/formononetin-attenuates-a%C3%AE-25-35-induced-cytotoxicity-in-ht22-cells-via-pi3k-akt-signaling-and-non-amyloidogenic-cleavage-of-app
#18
Lizhi Chen, Shanshan Ou, Lingqi Zhou, Hai Tang, Jie Xu, Kaihua Guo
Amyloid beta (Aβ) is the main component of the amyloid plaques that accumulate in the brains of Alzheimer patients. Here, we reported the protective role of Formononetin (Form) against Aβ25-35-induced neurotoxicity in HT22 cells. We found that Form significantly increased the viability of HT22 cells but decreased the cell apoptosis when challenging with Aβ25-35. The inhibitory effects of Form were associated with PI3K/Akt signaling pathway as PI3K inhibitor (LY294002) or ERα specific inhibitor (MPP) blocked the effects...
February 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27929541/non-amyloidogenic-effects-of-%C3%AE-2-adrenergic-agonists-implications-for-brimonidine-mediated-neuroprotection
#19
Shereen Nizari, Li Guo, Benjamin M Davis, Eduardo M Normando, Joana Galvao, Lisa A Turner, Mukhtar Bizrah, Mohammad Dehabadi, Kailin Tian, M Francesca Cordeiro
The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27825720/ginsenoside-rd-promotes-non-amyloidogenic-pathway-of-amyloid-precursor-protein-processing-by-regulating-phosphorylation-of-estrogen-receptor-alpha
#20
Xiaodong Yan, Gengyao Hu, Weiming Yan, Tao Chen, Feng Yang, Xiao Zhang, Gang Zhao, Juanfang Liu
AIMS: Previous study demonstrated that Ginsenoside Rd. (GS-Rd) could improve cognitive and memory function in animal model of Alzheimer's disease. This study was aimed to investigate whether GS-Rd could improve non-amyloidogenic pathway by activating estrogen receptor (ER). MAIN METHODS: 10mg/kg GS-Rd in ovariectomy (OVX)+GS-Rd group and equivalent volume of saline in sham operated group and OVX group were administrated intraperitoneally for two months, respectively...
January 1, 2017: Life Sciences
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