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https://www.readbyqxmd.com/read/29619739/7-deoxy-trans-dihydronarciclasine-reduces-%C3%AE-amyloid-and-ameliorates-memory-impairment-in-a-transgenic-model-of-alzheimer-s-disease
#1
Yoon Sun Chun, Lijun Zhang, Huan Li, Yurim Park, Sungkwon Chung, Hyun Ok Yang
The critical pathological feature of Alzheimer's disease (AD) is the accumulation of β-amyloid (Aβ), the main constituent of amyloid plaques. β-amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretase generating Aβ at endosomes or non-amyloidogenic processing by α-secretase precluding the production of Aβ at the plasma membrane. Recently, several natural products have been widely researched on the prevention of Aβ accumulation for AD treatment. We previously reported that Lycoris chejuensis K...
April 4, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29616709/development-of-azeliragon-an-oral-small-molecule-antagonist-of-the-receptor-for-advanced-glycation-endproducts-for-the-potential-slowing-of-loss-of-cognition-in-mild-alzheimer-s-disease
#2
A H Burstein, M Sabbagh, R Andrews, C Valcarce, I Dunn, L Altstiel
Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer's disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow...
2018: Journal of Prevention of Alzheimer's Disease
https://www.readbyqxmd.com/read/29615891/catalpol-inhibits-amyloid-%C3%AE-generation-through-promoting-%C3%AE-cleavage-of-app-in-swedish-mutant-app-overexpressed-n2a-cells
#3
Zhuo Wang, Xueshi Huang, Pu Zhao, Limei Zhao, Zhan-You Wang
Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD), due to its neurotoxicity. Thus, blocking Aβ generation and aggregation in the brain has been realized as an efficient way for the prevention of AD. The natural product catalpol, isolated from Rehmannia glutinosa , has shown neuroprotective activities through inhibiting soluble Aβ production, degrading Aβ peptide, and attenuating Aβ toxicity and neuroinflammatory responses. In the present study, we aimed to evaluate whether catalpol reduce Aβ generation associated with regulating amyloid precursor protein (APP) proteolytic processing...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29611102/11%C3%AE-hsd1-inhibition-by-rl-118-promotes-autophagy-and-correlates-with-reduced-oxidative-stress-and-inflammation-enhancing-cognitive-performance-in-samp8-mouse-model
#4
Dolors Puigoriol-Illamola, Christian Griñán-Ferré, Foteini Vasilopoulou, Rosana Leiva, Santiago Vázquez, Mercè Pallàs
Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction...
April 2, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29563326/extending-a-systems-model-of-the-app-pathway-separation-of-%C3%AE-and-%C3%AE-secretase-sequential-cleavage-steps-of-app
#5
Eline T S van Maanen, Tamara S van Steeg, Maurice Ahsman, Maria S Michener, Mary J Savage, Matthew E Kennedy, Huub J Kleijn, Julie A Stone, Meindert Danhof
The abnormal accumulation of amyloid-β (Aβ) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the APP pathway, describing the Aβ precursor protein (APP) metabolite responses (Aβ40, Aβ42, sAPPα and sAPPβ) to β-secretase 1 (BACE1) inhibition (van Maanen et al., 2016). In this investigation this model was challenged to describe Aβ dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aβ response to their respective inhibition...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29560732/human-umbilical-cord-blood-serum-derived-%C3%AE-secretase-functional-testing-in-alzheimer-s-disease-mouse-models
#6
Ahsan Habib, Huayan Hou, Takashi Mori, Jun Tian, Jin Zeng, Shengnuo Fan, Brian Giunta, Paul R Sanberg, Darrell Sawmiller, Jun Tan
Alzheimer's disease (AD) is an age-related disorder that affects cognition. Our previous studies showed that the neuroprotective fragment of amyloid procurer protein (APP) metabolite, soluble APPα (sAPPα), interferes with β-site APP-cleaving enzyme 1 (BACE1, β-secretase) cleavage and reduces amyloid-β (Aβ) generation. In an attempt to identify approaches to restore sAPPα levels, we found that human cord blood serum (CBS) significantly promotes sAPPα production compared with adult blood serum (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells stably expressing wild-type human APP...
January 1, 2018: Cell Transplantation
https://www.readbyqxmd.com/read/29478851/drosophila-full-length-amyloid-precursor-protein-is-required-for-visual-working-memory-and-prevents-age-related-memory-impairment
#7
Franziska Rieche, Katia Carmine-Simmen, Burkhard Poeck, Doris Kretzschmar, Roland Strauss
The β-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPPβ fragments and the APP intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted sAPPα fragments and the identical AICD...
March 5, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29466703/sapp%C3%AE-and-sapp%C3%AE-increase-structural-complexity-and-e-i-input-ratio-in-primary-hippocampal-neurons-and-alter-ca-2-homeostasis-and-creb1-signaling
#8
Raphael Hesse, Bjoern von Einem, Franziska Wagner, Patricia Bott, Daniel Schwanzar, Rosemary J Jackson, Karl Josef Föhr, Ludwig Lausser, Katja S Kroker, Christian Proepper, Paul Walther, Hans A Kestler, Tara L Spires-Jones, Tobias Boeckers, Holger Rosenbrock, Christine A F von Arnim
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist...
June 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29426354/lentivirus-mediated-expression-of-human-secreted-amyloid-precursor-protein-alpha-prevents-development-of-memory-and-plasticity-deficits-in-a-mouse-model-of-alzheimer-s-disease
#9
Valerie T Y Tan, Bruce G Mockett, Shane M Ohline, Karen D Parfitt, Hollie E Wicky, Katie Peppercorn, Lucia Schoderboeck, Mohamad Fairuz Bin Yahaya, Warren P Tate, Stephanie M Hughes, Wickliffe C Abraham
Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-β peptide (Aβ). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPα), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Αβ, sAPPα has many neuroprotective and neurotrophic properties. Increasing sAPPα levels has the potential to serve as a therapeutic treatment that mitigates the effects of Aβ and rescue cognitive function...
February 9, 2018: Molecular Brain
https://www.readbyqxmd.com/read/29410317/secreted-amyloid-precursor-protein-alpha-activates-neuronal-insulin-receptors-and-prevents-diabetes-induced-encephalopathy
#10
Brent D Aulston, Jason Schapansky, YaWen Huang, Gary L Odero, Gordon W Glazner
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals...
May 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29383688/role-of-amyloid-precursor-protein-app-and-its-derivatives-in-the-biology-and-cell-fate-specification-of-neural-stem-cells
#11
REVIEW
Raquel Coronel, Adela Bernabeu-Zornoza, Charlotte Palmer, Mar Muñiz-Moreno, Alberto Zambrano, Eva Cano, Isabel Liste
Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP...
January 30, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29382156/alpha-secretase-adam10-regulation-insights-into-alzheimer-s-disease-treatment
#12
REVIEW
Rafaela Peron, Izabela Pereira Vatanabe, Patricia Regina Manzine, Antoni Camins, Márcia Regina Cominetti
ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer's disease (AD)...
January 29, 2018: Pharmaceuticals
https://www.readbyqxmd.com/read/29348391/effects-of-senescence-and-angiotensin-ii-on-expression-and-processing-of-amyloid-precursor-protein-in-human-cerebral-microvascular-endothelial-cells
#13
Ruohan Sun, Tongrong He, Yujun Pan, Zvonimir S Katusic
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression...
January 15, 2018: Aging
https://www.readbyqxmd.com/read/29337689/a%C3%AE-42-oligomers-impair-the-bioenergetic-activity-in-hippocampal-synaptosomes-derived-from-app-ko-mice
#14
Benedikt Beckert, Amparo Acker-Palmer, Walter Volknandt
Employing hippocampal synaptosomes from amyloid precursor protein (APP)-deleted mice we analyzed the immediate effects of amyloid beta peptide 42 (Aβ42) peptide in its oligomeric or fibrillar assembly or of soluble amyloid precursor protein alpha (sAPPα) protein on their bioenergetic activity. Upon administration of oligomeric Aβ42 peptide for 30 min we observed a robust decrease both in mitochondrial activity and in mitochondrial membrane potential (MMP). In contrast the respective fibrillary or scrambled peptides showed no effect, indicating that inhibition strictly depends on the oligomerization status of the peptide...
April 25, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29251519/impairment-of-amyloid-precursor-protein-alpha-processing-in-cerebral-microvessels-of-type-1-diabetic-mice
#15
Tongrong He, Ruohan Sun, Anantha Vr Santhanam, Livius V d'Uscio, Tong Lu, Zvonimir S Katusic
The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2 )...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29163135/neuroprotective-effect-of-ligustilide-through-induction-of-%C3%AE-secretase-processing-of-both-app-and-klotho-in-a-mouse-model-of-alzheimer-s-disease
#16
Xi Kuang, Hong-Jing Zhou, Amy H Thorne, Xi-Nan Chen, Lin-Jiao Li, Jun-Rong Du
Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer's disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29149631/prostaglandin-j2-promotes-o-glcnacylation-raising-app-processing-by-%C3%AE-and-%C3%AE-secretases-relevance-to-alzheimer-s-disease
#17
Teneka Jean-Louis, Patricia Rockwell, Maria E Figueiredo-Pereira
Regulation of the amyloid precursor protein (APP) processing by α- and β-secretases is of special interest to Alzheimer's disease (AD), as these proteases prevent or mediate amyloid beta formation, respectively. Neuroinflammation is also implicated in AD. Our data demonstrate that the endogenous mediator of inflammation prostaglandin J2 (PGJ2) promotes full-length APP (FL-APP) processing by α- and β-secretases. The decrease in FL-APP was independent of proteasomal, lysosomal, calpain, caspase, and γ-secretase activities...
February 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29073110/m344-promotes-nonamyloidogenic-amyloid-precursor-protein-processing-while-normalizing-alzheimer-s-disease-genes-and-improving-memory
#18
Claude-Henry Volmar, Hasib Salah-Uddin, Karolina J Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, Nidhi H Patel, Gregory C Sartor, Neil Mehta, Nancy T H Miles, Sachi Desse, David Dorcius, Michael D Cameron, Shaun P Brothers, Claes Wahlestedt
Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29063514/biomarkers-of-neuronal-injury-and-amyloid-metabolism-in-the-cerebrospinal-fluid-of-patients-infected-with-hiv-1-subtypes-b-and-c
#19
Sérgio Monteiro de Almeida, Clea E Ribeiro, Indianara Rotta, Mauro Piovesan, Bin Tang, Florin Vaida, Sonia Mara Raboni, Scott Letendre, Michael Potter, Meire S Batistela Fernandes, Ronald J Ellis
Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau181 ), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression...
February 2018: Journal of Neurovirology
https://www.readbyqxmd.com/read/29032190/transient-increase-in-sapp%C3%AE-secretion-in-response-to-a%C3%AE-1-42-oligomers-an-attempt-of-neuronal-self-defense
#20
Christiane Rose, Emilie Dorard, Mickael Audrain, Lucie Gorisse-Hussonnois, Nathalie Cartier, Jérome Braudeau, Bernadette Allinquant
Amyloid precursor protein (APP), a key molecule of Alzheimer disease, is metabolized in 2 antagonist pathways generating the soluble APP alpha (sAPPα) having neuroprotective properties and the beta amyloid (Aβ) peptide at the origin of neurotoxic oligomers, particularly Aβ1-42. Whether extracellular Aβ1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aβ1-42 oligomers to primary cortical neurons induced a transient increase in α-secretase activity and secreted sAPPα 6-9 hours later...
January 2018: Neurobiology of Aging
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