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amyloid precursor protein

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https://www.readbyqxmd.com/read/28550267/amyloid-precursor-protein-haploinsufficiency-preferentially-mediates-brain-iron-accumulation-in-mice-transgenic-for-the-huntington-s-disease-mutation
#1
Kiersten Berggren, Sonal Agrawal, Julia A Fox, Justin Hildenbrand, Ryan Nelson, Ashley I Bush, Jonathan H Fox
BACKGROUND: Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. OBJECTIVE: To determine the effects of APP insufficiency on HD in YAC128 mice. METHODS: We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny...
May 24, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28544119/common-fibril-structures-imply-systemically-conserved-protein-misfolding-pathways-in%C3%A2-vivo
#2
Karthikeyan Annamalai, Falk Liberta, Marie-Theres Vielberg, William Close, Hauke Lilie, Karl-Heinz Gührs, Angelika Schierhorn, Rolf Koehler, Andreas Schmidt, Christian Haupt, Ute Hegenbart, Stefan Schönland, Matthias Schmidt, Michael Groll, Marcus Fändrich
Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post-translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril...
May 23, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28540926/entorhinal-cortical-deep-brain-stimulation-rescues-memory-deficits-in-both-young-and-old-mice-genetically-engineered-to-model-alzheimer-s-disease
#3
Frances Xia, Adelaide Yiu, Scellig Sd Stone, Soojin Oh, Andres M Lozano, Sheena A Josselyn, Paul W Frankland
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Deep brain stimulation (DBS) has been used to treat a variety of brain disorders and shows promise in alleviating cognitive symptoms in some AD patients (Laxton et al., 2010). We previously showed that DBS of the entorhinal cortex (EC) enhances spatial memory formation in normal (wild-type) mice (Stone et al., 2011). Here we tested the effects of EC-DBS on the progressive cognitive deficits in a genetically-based mouse model of AD...
May 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28539872/the-role-of-app-in-structural-spine-plasticity
#4
REVIEW
Elena Montagna, Mario M Dorostkar, Jochen Herms
Amyloid precursor protein (APP) is a transmembrane protein highly expressed in neurons. The full-length protein has cell-adhesion and receptor-like properties, which play roles in synapse formation and stability. Furthermore, APP can be cleaved by several proteases into numerous fragments, many of which affect synaptic function and stability. This review article focuses on the mechanisms of APP in structural spine plasticity, which encompasses the morphological alterations at excitatory synapses. These occur as changes in the number and morphology of dendritic spines, which correspond to the postsynaptic compartment of excitatory synapses...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28539479/%C3%AE-secretase-inhibitors-in-cancer-clinical-trials-are-pharmacologically-and-functionally-distinct
#5
Yong Ran, Fokhrul Hossain, Antonio Pannuti, Christian B Lessard, Gabriela Z Ladd, Joo In Jung, Lisa M Minter, Barbara A Osborne, Lucio Miele, Todd E Golde
γ-Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members...
May 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28539221/lodopyridones-b-and-c-from-a-marine-sediment-derived-bacterium-saccharomonospora-sp
#6
Tu Cam Le, Chae-Yoon Yim, Songhee Park, Nikita Katila, Inho Yang, Myeong Chong Song, Yeo Joon Yoon, Dong-Young Choi, Hyukjae Choi, Sang-Jip Nam, William Fenical
HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (1 and 2) along with the previously reported lodopyridone A (3). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (3). Lodopyridones B and C (1 and 2) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules...
May 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28537903/amyloid-precursor-like-protein-1-promotes-jnk-mediated-cell-migration-in-drosophila
#7
Xingjun Wang, Ying Sun, Shilong Han, Chenxi Wu, Yeqing Ma, Yu Zhao, Yingyao Shao, Yujun Chen, Lingzhi Kong, Wenzhe Li, Fan Zhang, Lei Xue
The amyloid precursor like protein-1 (APLP1) is a member of the amyloid precursor protein (APP) family in mammals. While many studies have been focused on the pathologic role of APP in Alzheimer's disease, the physiological functions of APLP1 have remained largely elusive. Here we report that ectopic expression of APLP1 in Drosophila induces cell migration, which is suppressed by the loss of JNK signaling and enhanced by the gain of JNK signaling. APLP1 activates JNK signaling through phosphorylation of JNK, which up-regulates the expression of matrix metalloproteinase MMP1 required for basement membranes degradation and promotes actin remodeling essential for cell migration...
May 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28533411/bidirectional-regulation-of-a%C3%AE-levels-by-presenilin-1
#8
Victor Bustos, Maria V Pulina, Yildiz Kelahmetoglu, Subhash C Sinha, Fred S Gorelick, Marc Flajolet, Paul Greengard
Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533191/mir-34a-knockout-attenuates-cognitive-deficits-in-app-ps1-mice-through-inhibition-of-the-amyloidogenic-processing-of-app
#9
Chongdong Jian, Mengru Lu, Zhao Zhang, Long Liu, Xianfeng Li, Fang Huang, Ning Xu, Lina Qin, Qian Zhang, Donghua Zou
The noncoding miRNA-34a (miR-34a) is involved in Alzheimer's disease (AD) pathologenesis and shows potential for application as a biomarker for early diagnosis and intervention. Here, we established miR-34a knockout mice in an APP/PS1 background (APP/PS1-miR-34a KO mice) by crossbreeding miR-34a(-/-) mice with APP/PS1 mice. We then investigated cognitive impairment and related pathologies. The results showed that the level of miR-34a was increased at about 6months in APP/PS1 mice, consistent with the increase in amyloid β (Aβ), and cognitive function was significantly improved in mice when miR-34a was knocked out in 9-month-old and 12-month-old mice, indicating that miR-34a is a potential candidate for determining the progression of AD...
May 19, 2017: Life Sciences
https://www.readbyqxmd.com/read/28528772/early-interleukin-6-enhances-hepatic-ketogenesis-in-appswe-psen1de9-mice-via-3-hydroxy-3-methylglutary-coa-synthase-2-signaling-activation-by-p38-nuclear-factor-%C3%AE%C2%BAb-p65
#10
Le Shi, Daina Zhao, Chen Hou, Yunhua Peng, Jing Liu, Shuangxi Zhang, Jiankang Liu, Jiangang Long
Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APPSWE) and presenilin (PSEN1dE9) (APP/PS1) mice...
April 26, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28528321/omega-3-fatty-acids-lipids-and-apoe-lipidation-in-alzheimer-s-disease-a-rationale-for-multi-nutrient-dementia-prevention
#11
Marcus O Grimm, Daniel Michaelson, Tobias Hartmann
In the last decade it has become obvious that Alzheimer's disease (AD) is closely linked to changes in lipids or lipid metabolism. One of the main pathological hallmarks of AD is amyloid-β (Aβ) deposition. Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP). Interestingly, both, the APP and all APP secretases are transmembrane proteins which cleave APP close to and in the lipid bilayer. Moreover, apolipoprotein E4 (apoE4) has been identified as the most prevalent genetic risk factor for AD...
May 20, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28528185/simvastatin-ameliorate-memory-deficits-and-inflammation-in-clinical-and-mouse-model-of-alzheimer-s-disease-via-modulating-the-expression-of-mir-106b
#12
Wenzhong Huang, Zhenyu Li, Liandong Zhao, Wei Zhao
BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored. METHODS: First, we tested the effect of simvastatin on AD in clinical research...
May 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28527217/protein-phosphorylation-is-a-key-mechanism-in-alzheimer-s-disease
#13
Joana Oliveira, Márcio Costa, Maria Soares Cachide de Almeida, Odete A B da Cruz E Silva, Ana Gabriela Henriques
Altered protein phosphorylation states of several proteins are closely associated with Alzheimer's disease (AD). Among these are the amyloid-β precursor protein (AβPP) and the tau protein. In fact, altered protein phosphorylation states already provide strong biomarkers for AD diagnosis, as is the case with hyperphosphorylated tau. It follows that modulating signaling cascades provides an attractive avenue for exploring novel therapeutic strategies. This review focuses on some of the major protein kinases and protein phosphatases relevant to AD...
May 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28526617/cyclin-dependent-kinase-5-a-novel-avenue-for-alzheimer-s-disease
#14
REVIEW
Anisha S Bhounsule, Lokesh Kumar Bhatt, Kedar S Prabhavalkar, Manisha Oza
Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD...
May 17, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28523372/dietary-eicosapentaenoic-acid-normalizes-hippocampal-omega-3-and-6-polyunsaturated-fatty-acid-profile-attenuates-glial-activation-and-regulates-bdnf-function-in-a-rodent-model-of-neuroinflammation-induced-by-central-interleukin-1%C3%AE-administration
#15
Yilong Dong, Min Xu, Allan V Kalueff, Cai Song
PURPOSE: Interleukin (IL)-1β can activate glial cells to trigger neuroinflammation and neurodegeneration. Lower omega (n)-3 polyunsaturated fatty acids (PUFAs) and lower n-3/n-6 PUFA ratios occur in the brain of patients with Alzheimer's disease (AD). We have previously reported that an n-3 PUFA, eicosapentaenoic acid (EPA), can improve memory and attenuate neurodegeneration-like changes in animal models of AD. However, whether and how EPA modulates glial cell activity and functions remains unclear...
May 18, 2017: European Journal of Nutrition
https://www.readbyqxmd.com/read/28521611/sgpl1-sphingosine-phosphate-lyase-1-modulates-neuronal-autophagy-via-phosphatidylethanolamine-production
#16
Daniel N Mitroi, Indulekha Karunakaran, Markus Gräler, Julie D Saba, Dan Ehninger, María Dolores Ledesma, Gerhild van Echten-Deckert
Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons. SGPL1 cleaves S1P into ethanolamine phosphate, which is directed toward the synthesis of phosphatidylethanolamine (PE) that anchors LC3-I to phagophore membranes in the form of LC3-II...
May 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28520784/presynaptic-a%C3%AE-40-prevents-synapse-addition-in-the-adult-drosophila-neuromuscular-junction
#17
Begoña López-Arias, Enrique Turiégano, Ignacio Monedero, Inmaculada Canal, Laura Torroja
Complexity in the processing of the Amyloid Precursor Protein, which generates a mixture of βamyloid peptides, lies beneath the difficulty in understanding the etiology of Alzheimer's disease. Moreover, whether Aβ peptides have any physiological role in neurons is an unresolved question. By expressing single, defined Aβ peptides in Drosophila, specific effects can be discriminated in vivo. Here, we show that in the adult neuromuscular junction (NMJ), presynaptic expression of Aβ40 hinders the synaptic addition that normally occurs in adults, yielding NMJs with an invariable number of active zones at all ages tested...
2017: PloS One
https://www.readbyqxmd.com/read/28519902/reduced-gliotransmitter-release-from-astrocytes-mediates-tau-induced-synaptic-dysfunction-in-cultured-hippocampal-neurons
#18
Roberto Piacentini, Domenica Donatella Li Puma, Marco Mainardi, Giacomo Lazzarino, Barbara Tavazzi, Ottavio Arancio, Claudio Grassi
Tau is a microtubule-associated protein exerting several physiological functions in neurons. In Alzheimer's disease (AD) misfolded tau accumulates intraneuronally and leads to axonal degeneration. However, tau has also been found in the extracellular medium. Recent studies indicated that extracellular tau uploaded from neurons causes synaptic dysfunction and contributes to tau pathology propagation. Here we report novel evidence that extracellular tau oligomers are abundantly and rapidly accumulated in astrocytes where they disrupt intracellular Ca(2+) signaling and Ca(2+) -dependent release of gliotransmitters, especially ATP...
May 18, 2017: Glia
https://www.readbyqxmd.com/read/28515043/brain-perivascular-macrophages-initiate-the-neurovascular-dysfunction-of-alzheimer-a%C3%AE-peptides
#19
Laibaik Park, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pitstick, Linda H Younkin, Steven G Younkin, Ping Zhou, Geroge A Carlson, Josef Anrather, Costantino Iadecola
Rationale: Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer's disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS)...
May 17, 2017: Circulation Research
https://www.readbyqxmd.com/read/28513774/hippocampal-overexpression-of-down-syndrome-cell-adhesion-molecule-in-amyloid-precursor-protein-transgenic-mice
#20
Y L Jia, Z X Fu, B H Zhang, Y J Jia
Down syndrome cell adhesion molecule (DSCAM) is located within the Down syndrome critical region of chromosome 21. DSCAM is a broadly expressed neurodevelopmental protein involved in synaptogenesis, neurite outgrowth, and axon guidance. We previously demonstrated DSCAM overexpression in the cortex of amyloid precursor protein (APP) transgenic mice, suggesting possible regulatory interactions between APP and DSCAM. APP mice exhibit deficits in hippocampus-dependent learning and memory. In this preliminary study, we examined age-related changes in DSCAM expression within the hippocampus in 16 APP transgenic mice (1, 3, 6 and 12 months old)...
May 15, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
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