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amyloid precursor protein

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https://www.readbyqxmd.com/read/28636676/mitochondrion-to-endoplasmic-reticulum-apposition-length-in-zebrafish-embryo-spinal-progenitors-is-unchanged-in-response-to-perturbations-associated-with-alzheimer-s-disease
#1
Morgan Newman, Lena Halter, Anne Lim, Michael Lardelli
Mutations in the human genes PRESENILIN1 (PSEN1), PRESENILIN2 (PSEN2) and AMYLOID BETA A4 PRECURSOR PROTEIN (APP) have been identified in familial Alzheimer's disease (AD). The length of mitochondrion-endoplasmic reticulum (M-ER) appositions is increased in Psen1-/-/Psen2-/- double knockout murine embryonic fibroblasts and in fibroblasts from AD-affected individuals. Development of an easily accessible, genetically manipulable, in vivo system for studying M-ER appositions would be valuable so we attempted to manipulate M-ER apposition length in zebrafish (Danio rerio) embryos...
2017: PloS One
https://www.readbyqxmd.com/read/28634550/sortilin-related-receptor-expression-in-human-neural-stem-cells-derived-from-alzheimer-s-disease-patients-carrying-the-apoe-epsilon-4-allele
#2
Alen Zollo, Zoe Allen, Helle F Rasmussen, Filomena Iannuzzi, Yichen Shi, Agnete Larsen, Thorsten J Maier, Carmela Matrone
Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28632419/in-vitro-co-expression-of-human-amyloidogenic-immunoglobulin-light-and-heavy-chain-proteins-a-relevant-cell-based-model-of-al-amyloidosis
#3
Elena S Klimtchuk, Tatiana B Prokaeva, Brian H Spencer, Olga Gursky, Lawreen H Connors
Immunoglobulin (Ig) light chain (LC) amyloidosis (AL) is characterized by the overproduction and tissue deposition of monoclonal LC in various organs and tissues. The plasma circulating monoclonal LC is believed to be the precursor of the deposited protein and in vitro studies aimed at understanding AL pathobiology have mainly focused on LC and its variable domain. While 33% of patients have free circulating monoclonal LC, ∼40% feature LC complexed to heavy chain (HC) forming a monoclonal intact Ig; the significance of free vs...
June 20, 2017: Amyloid: the International Journal of Experimental and Clinical Investigation
https://www.readbyqxmd.com/read/28632177/the-intersection-of-ngf-trka-signaling-and-amyloid-precursor-protein-processing-in-alzheimer-s-disease-neuropathology
#4
REVIEW
Nadia Canu, Giuseppina Amadoro, Viviana Triaca, Valentina Latina, Valentina Sposato, Veronica Corsetti, Cinzia Severini, Maria Teresa Ciotti, Pietro Calissano
Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology...
June 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28628788/cryo-em-structures-of-human-%C3%AE-secretase
#5
REVIEW
Guanghui Yang, Rui Zhou, Yigong Shi
γ-secretase, a membrane-embedded aspartate protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of β-amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD-associated mutations are mapped to presenilin 1 (PS1), the catalytic component of γ-secretase. In the past three years, several cryo-electron microscopy (cryo-EM) structures of human γ-secretase have been determined at near atomic resolutions...
June 16, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28627692/the-role-of-intestinal-endotoxemia-in-a-rat-model-of-aluminum-neurotoxicity
#6
Feng Wang, Rui-Xia Guo, Wen-Xing Li, Bao-Feng Yu, Bai Han, Li-Xin Liu, De-Wu Han
The present study aimed to investigate the effects of intestinal endotoxemia (IETM) in a rat model of aluminum neurotoxicity established by D-galactose and aluminum trichloride (AlCl3). Adult Wistar rats were administered D‑galactose and AlCl3 to create the aluminum neurotoxicity model. The learning and memory abilities of the rats were subsequently observed using a Morris water maze test and the serum levels of lipopolysaccharide (LPS), tumor necrosis factor (TNF)‑α, interleukin (IL)‑1, diamine oxidase (DAO), glutamine (Gln) and glutaminase were measured...
June 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28626017/amyloid-beta-peptide-is-needed-for-cgmp-induced-long-term-potentiation-and-memory
#7
Agostino Palmeri, Roberta Ricciarelli, Walter Gulisano, Daniela Rivera, Claudia Rebosio, Elisa Calcagno, Maria Rosaria Tropea, Silvia Conti, Utpal Das, Subhojit Roy, Maria A Pronzato, Ottavio Arancio, Ernesto Fedele, Daniela Puzzo
High levels of amyloid-beta peptide (Aβ) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aβ are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aβ levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors (PDE5-Is) sildenafil and vardenafil induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1 (BACE1)...
June 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28626014/bace1-cleavage-site-selection-critical-for-amyloidogenesis-and-alzheimer-s-pathogenesis
#8
Shuting Zhang, Zhe Wang, Fang Cai, Mingming Zhang, Yili Wu, Jing Zhang, Weihong Song
Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's Disease (AD) or protecting against dementia. Under normal conditions beta-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp(1) site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu(11) site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu(11) site to the Asp(1) site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio...
June 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28624505/deficiency-in-ep4-receptor-associated-protein-ameliorates-abnormal-anxiety-like-behavior-and-brain-inflammation-in-a-mouse-model-of-alzheimer-disease
#9
Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Masayuki Yokode, Manabu Minami
Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20(+/-) onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20(+/-)EPRAP(+/+) and J20(+/-)EPRAP(-/-) mice...
June 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28624365/o-glcnacylation-of-amyloid-%C3%AE-precursor-protein-at-threonine-576-residue-regulates-trafficking-and-processing
#10
Yoon Sun Chun, Oh-Hoon Kwon, Sungkwon Chung
The pathological hallmark of Alzheimer's disease (AD) is associated with the accumulation of amyloid-β (Aβ) derived from proteolytic processing of amyloid-β precursor protein (APP). APP undergoes post-translational modification including N- and O-glycosylation. O-GlcNAcylation is a novel type of O-glycosylation, mediated by O-GlcNAc transferase attaching O-β-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of the target proteins. O-GlcNAc is removed by O-GlcNAcase. We have previously reported that increasing O-GlcNAcylated APP using the O-GlcNAcase inhibitor, PUGNAc, increases its trafficking rate to the plasma membrane and decreases its endocytosis rate, resulting in decreased Aβ production...
June 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28623607/presenilin-1-targeted-morpholino-induces-cognitive-deficits-increased-brain-a%C3%AE-1-42-and-decreased-synaptic-marker-psd-95-in-zebrafish-larvae
#11
Laura Roesler Nery, Natalia Eltz Silva, Raphaela Fonseca, Monica Ryff Moreira Vianna
Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the γ-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid-β (Aβ) peptides of varying lengths. Presenilin-1 gene (psen1) mutations are the main cause of early-onset autosomal-dominant Familial Alzheimer Disease. Elucidating the roles of Presenilin-1 and other hallmark proteins involved in Alzheimer's disease is crucial for understanding the disease etiology and underlying molecular mechanisms...
June 16, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28622692/motor-deficits-are-independent-of-axonopathy-in-an-alzheimer-s-disease-mouse-model-of-tgcrnd8-mice
#12
Qiuju Yuan, Jian Yang, Wutian Wu, Zhi-Xiu Lin
There have been an increasing number of reports of non-cognitive symptoms in Alzheimer's disease (AD). Some symptoms are associated with the loss of motor functions, e.g. gait disturbances, disturbed activity level and balance. Consistent with clinical findings, several AD mouse models harboring amyloid pathology develop motor impairment. Although the factors that contribute to the motor deficits have not yet been determined, it has been suggested that axonopathy is one of the key factors that may contribute to this particular feature of the disease...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28621903/histological-assessment-of-%C3%AE-amyloid-precursor-protein-immunolabelled-rectal-biopsies-aids-diagnosis-of-equine-grass-sickness
#13
R C Jago, S Scholes, T S Mair, G R Pearson, R S Pirie, I Handel, E M Milne, F Coyle, B C McGorum
BACKGROUND: An accurate, minimally invasive, ante mortem, diagnostic test for equine grass sickness (EGS) is currently lacking. While histological examination of haematoxylin-eosin stained rectal biopsies for chromatolytic neurons is insensitive as a diagnostic test for EGS, we hypothesised that the diagnostic accuracy could be improved by immunolabelling for β-amyloid precursor protein (β-APP) which has increased expression in cranial cervical ganglia (CCG) neuronal perikarya in EGS...
June 16, 2017: Equine Veterinary Journal
https://www.readbyqxmd.com/read/28620801/fty720-attenuates-infection-induced-enhancement-of-a%C3%AE-accumulation-in-app-ps1-mice-by-modulating-astrocytic-activation
#14
Róisín M McManus, Orla M Finucane, Mieszko M Wilk, Kingston H G Mills, Marina A Lynch
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD...
June 15, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28618005/bace1-inhibitor-lanabecestat-azd3293-in-a-phase-1-study-of-healthy-japanese-subjects-pharmacokinetics-and-effects-on-plasma-and-cerebrospinal-fluid-a%C3%AE-peptides
#15
Kei Sakamoto, Shunji Matsuki, Kyoko Matsuguma, Tatsuya Yoshihara, Naoki Uchida, Fumihiko Azuma, Muir Russell, Glen Hughes, Samantha Budd Haeberlein, Robert C Alexander, Susanna Eketjäll, Alan R Kugler
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28617802/oxidative-stress-affects-processing-of-amyloid-precursor-protein-in-vascular-endothelial-cells
#16
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/28613962/significant-association-between-renal-function-and-area-of-amyloid-deposition-in-kidney-biopsy-specimens-in-both-aa-amyloidosis-associated-with-rheumatoid-arthritis-and-al-amyloidosis
#17
Takeshi Kuroda, Naohito Tanabe, Eriko Hasegawa, Ayako Wakamatsu, Yukiko Nozawa, Hiroe Sato, Takeshi Nakatsue, Yoko Wada, Yumi Ito, Naofumi Imai, Mitsuhiro Ueno, Masaaki Nakano, Ichiei Narita
The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues...
June 14, 2017: Amyloid: the International Journal of Experimental and Clinical Investigation
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
#18
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/28611242/evaluation-of-%C3%AE-pet-outcome-measures-to-detect-disease-modification-induced-by-bace-inhibition-in-a-transgenic-mouse-model-of-alzheimer-s-disease
#19
Steven Deleye, Ann Marie Waldron, Jeroen Verhaeghe, Astrid Bottelbergs, Leonie Wyffels, Bianca Van Broeck, Xavier Langlois, Mark E Schmidt, Sigrid Stroobants, Steven Staelens
Purpose: In this study, we investigated the effects of chronic administration of an inhibitor of the β-site amyloid precursor protein -cleaving enzyme 1 (BACE1) on Alzheimer's- related pathology by multi-tracer positron emission tomography (PET) imaging in APPPS1-21 mice. Methods: Wild-type (WT) and APPPS1-21 (TG) mice received vehicle (VEH) or BACE inhibitor (60 mg/kg) initiated at 7 weeks of age. Outcome measures of brain metabolism, neuroinflammation and amyloid-β pathology were obtained through μPET imaging with (18)F-FDG, (18)F-PBR111 and (18)F-AV45 respectively...
June 13, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28611024/platelet-amyloid-precursor-protein-is-a-modulator-of-venous-thromboembolism-in-mice
#20
Ilaria Canobbio, Caterina Visconte, Stefania Momi, Gianni Francesco Guidetti, Marta Zarà, Jessica Canino, Emanuela Falcinelli, Paolo Gresele, Mauro Torti
The amyloid precursor protein (APP), primarily known as the precursor of amyloid peptides that accumulate in the brain of Alzheimer's disease patients, is abundant in platelets but its physiological function remains unknown. In this study, we investigated the role of APP in hemostasis and thrombosis using APP knockout (KO) mice. Ex vivo aggregation, secretion, and integrin αIIbβ3 inside-out activation induced by several agonists were normal in APP-deficient platelets, but the number of circulating platelets was reduced by about 20%, and their size was slightly increased...
June 13, 2017: Blood
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