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APP transport

Kee-Chan Ahn, Cameron R Learman, Gary L Dunbar, Panchanan Maiti, Won-Cheoul Jang, Hyeon-Cheol Cha, Mee-Sook Song
Alzheimer's disease (AD) is defined by senile plaques, tauopathy and neuronal cell death in specific area of the brain. Recent studies suggest that neurovascular dysfunction may be an integral part of AD pathogenesis, contributing to the onset and development of AD pathologies such as neuronal death, inflammatory response, and breakdown of blood brain barrier (BBB). In addition, vascular complications caused by age-related metabolic diseases such as diabetes and high blood pressure have high incidence in development of dementia and AD...
May 16, 2018: Neuroscience
Robert Adalbert, Stefan Milde, Claire Durrant, Kunie Ando, Virginie Stygelbout, Zehra Yilmaz, Stacey Gould, Jean-Pierre Brion, Michael P Coleman
In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPTP301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPTP301L mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling...
April 5, 2018: Neurobiology of Aging
Wilhelm Stoffel, Britta Jenke, Inga Schmidt-Soltau, Erika Binczek, Susanne Brodesser, Ina Hammels
Neutral sphingomyelinase smpd3 is most abundantly expressed in neurons of brain. The function of SMPD3 has remained elusive. Here, we report a pathogenetic nexus between absence of SMPD3 in the Golgi compartment (GC) of neurons of the smpd3-/- mouse brain, inhibition of Golgi vesicular protein transport and progressive cognitive impairment. Absence of SMPD3 activity in the Golgi sphingomyelin cycle impedes remodeling of the lipid bilayer, essential for budding and multivesicular body formation. Importantly, we show that inhibition of the Golgi vesicular protein transport causes accumulation of neurotoxic proteins APP, Aβ and phosphorylated Tau, dysproteostasis, unfolded protein response, and apoptosis, which ultimately manifests in progressive cognitive decline, similar to the pathognomonic signatures of familial and sporadic forms of Alzheimer´s disease...
May 3, 2018: Cell Death & Disease
María Gabriela Otero, Ivan Fernandez Bessone, Alan Earle Hallberg, Lucas Eneas Cromberg, María Cecilia De Rossi, Trinidad M Saez, Valeria Levi, Angels Almenar-Queralt, Tomás Luis Falzone
Alzheimer Disease (AD) pathology includes the accumulation of poly-ubiquitinated proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. Using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescent cross-correlation analyses and membrane internalization blockage showed that plasma membrane APP do not contribute to transport defects...
May 3, 2018: Journal of Cell Science
Dingfeng Li, Juan Zhang, Ming Wang, Xiaohui Li, Huarui Gong, Huiping Tang, Lin Chen, Lili Wan, Qiang Liu
The ribosome is indispensable for precisely controlling the capacity of protein synthesis. However, how translational machinery is coordinated to meet the translational demands remains elusive. Here, we identify a nucleolar-specific lncRNA (LoNA), its 5' portion binds and sequesters nucleolin to suppress rRNA transcription, and its snoRNA like 3' end recruits and diminishes fibrillarin activity to reduce rRNA methylation. Activity-dependent decrease of LoNA leads to elevated rRNA and ribosome levels, an increased proportion of polysomes, mRNA polysome loading, and protein translation...
April 30, 2018: Nature Communications
Gerwyn Morris, Michael Berk, Michael Maes, Basant K Puri
The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD...
April 29, 2018: Molecular Neurobiology
Dorian Peters, Mark Deady, Nick Glozier, Samuel Harvey, Rafael A Calvo
BACKGROUND: Men are less likely to seek help for mental health problems, possibly because of stigma imposed by cultural masculine norms. These tendencies may be amplified within male-dominated workplaces such as the emergency services or transport industries. Mobile apps present a promising way to provide access to mental health support. However, little is known about the kinds of mental health technologies men would be willing to engage with, and no app can be effective if the intended users do not engage with it...
April 25, 2018: JMIR Mental Health
Luan Luu, Giuseppe D Ciccotosto, Laura J Vella, Lesley Cheng, Laila C Roisman, Gerhard Multhaup, Andrew F Hill, Lisa-Marie Munter, Roberto Cappai
The amyloid precursor protein (APP) undergoes extensive metabolism, and its transport and proteolytic processing can be modulated by its ability to form a homodimer. We have investigated the functional consequences of stabilised APP dimer expression in cells by studying the engineered dimerisation of the APPL17C (residue 17 in Aβ sequence) construct, which is associated with a 30% increase in APP dimer expression, on APP's neurite outgrowth promoting activity. Overexpression of APPL17C in SH-SY5Y cells decreased neurite outgrowth upon retinoic acid differentiation as compared to overexpressing APPWT cells...
April 19, 2018: Molecular Neurobiology
Raisa Z Freidlin, Amisha D Dave, Benjamin G Espey, Sean T Stanley, Marcial A Garmendia, Randall Pursley, Johnathon P Ehsani, Bruce G Simons-Morton, Thomas J Pohida
BACKGROUND: Naturalistic driving studies, designed to objectively assess driving behavior and outcomes, are conducted by equipping vehicles with dedicated instrumentation (eg, accelerometers, gyroscopes, Global Positioning System, and cameras) that provide continuous recording of acceleration, location, videos, and still images for eventual retrieval and analyses. However, this research is limited by several factors: the cost of equipment installation; management and storage of the large amounts of data collected; and data reduction, coding, and analyses...
April 19, 2018: JMIR MHealth and UHealth
Shengqi Dong, Xiaochen Huang, Jie Zhen, Nicholas Van Halm-Lutterodt, JiaJia Wang, Cui Zhou, Linhong Yuan
Quite a number of studies have examined the effects of fish oil supplementation on cognitive performance in different transgenic animal models of Alzheimer's disease (AD). However, inconsistent and controversial outcomes have been derived from these experiments. In order to investigate whether the beneficial effect of fish oil supplementation on cognition was dietary VE status associated, fish oil dietary intervention was carried out in transgenic APPswe /PS1dE9 (APP/PS1) mice. Control mice (C57BL/6J mice) were fed a normal control diet...
April 14, 2018: Molecular Neurobiology
Chia-Chia Lee, Ching-Pang Chang, Chun-Jung Lin, Hsing-Lin Lai, Yu-Han Kao, Sin-Jhong Cheng, Hui-Mei Chen, Yu-Ping Liao, Emilie Faivre, Luc Buée, David Blum, Jim-Min Fang, Yijuang Chern
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and synaptic dysfunction. Adenosine is an important homeostatic modulator that controls the bioenergetic network in the brain through regulating receptor-evoked signaling pathways, bioenergetic machineries, and epigenetic-mediated gene regulation. Equilibrative nucleoside transporter 1 (ENT1) is a major adenosine transporter that recycles adenosine from the extracellular space. In the present study, we report that a small adenosine analogue (designated J4) that inhibited ENT1 prevented the decline in spatial memory in an AD mouse model (APP/PS1)...
April 4, 2018: Molecular Neurobiology
Damian Robert Jenkins, Matthew J Craner, Margaret M Esiri, Gabriele C DeLuca
Traumatic brain injury is a leading cause of death and disability, particularly among the young. Despite this, no disease-specific treatments exist. Recently, descriptions of BBB disruption and parenchymal fibrinogen deposition have been reported in acute traumatic brain injury and in long-term survival; however, their contribution to the neuropathology of TBI remains unknown. 1, 2 The presence of fibrinogen - a well-documented activator of microglia/macrophages - may be associated with neuroinflammation, and neuronal/axonal injury...
April 2, 2018: Journal of Neurotrauma
Pablo Galeano, María C Leal, Carina C Ferrari, María C Dalmasso, Pamela V Martino Adami, María I Farías, Juan C Casabona, Mariana Puntel, Sonia Do Carmo, Clara Smal, Martín Arán, Eduardo M Castaño, Fernando J Pitossi, A Claudio Cuello, Laura Morelli
The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer's disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/-)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C)...
March 26, 2018: Molecular Neurobiology
Shishuang Zhang, Yongle Zhi, Fei Li, Shan Huang, Huabin Gao, Zhaoli Han, Xintong Ge, Dai Li, Fanglian Chen, Xiaodong Kong, Ping Lei
To date, the pathogenesis of Alzheimer's disease (AD) remains unclear. It is well-known that excessive deposition of Aβ in the brain is a crucial part of the pathogenesis of AD. In recent years, the AD neurovascular unit hypothesis has attracted much attention. Impairment of the blood-brain barrier (BBB) leads to abnormal amyloid-β (Aβ) transport, and chronic cerebral hypoperfusion causes Aβ deposition throughout the onset and progression of AD. Endothelial progenitor cells (EPCs) are the universal cells for repairing blood vessels...
April 15, 2018: Journal of the Neurological Sciences
Yijun Pan, Jennifer L Short, Stephanie A Newman, Kwok H C Choy, Durgesh Tiwari, Christopher Yap, Danielle Senyschyn, William A Banks, Joseph A Nicolazzo
Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. The brain clearance of intracerebroventricularly (icv) administered125 I-Aβ42 was assessed in male Swiss outbred mice administered daily oral NaCl or LiCl (300 mg/kg for 21 days)...
March 12, 2018: Brain, Behavior, and Immunity
Sanye Soroldoni, Ítalo Braga Castro, Fiamma Abreu, Fabio Andrei Duarte, Rodrigo Brasil Choueri, Osmar Olinto Möller, Gilberto Fillmann, Grasiela Lopes Leães Pinho
Sources, occurrence, composition and dynamics of antifouling paint particles (APPs) were assessed in Patos Lagoon estuary (PLE), Southern Brazil. Ten areas including boatyards, a marina and artisanal fishing harbors were identified in the estuarine system as potential sources of APPs. The APPs generated in these areas were highly heterogeneous considering the size, shape and composition. Based on an estimate of antifouling paint usage and amount of boats in each studied area, artisanal fishing harbors could be the main source of particles to PLE...
June 15, 2018: Water Research
I A Kuznetsov, A V Kuznetsov
We develop a mathematical model that enables us to investigate possible mechanisms by which two primary markers of Alzheimer's disease (AD), extracellular amyloid plaques and intracellular tangles, may be related. Our model investigates the possibility that the decay of anterograde axonal transport of amyloid precursor protein (APP), caused by toxic tau aggregates, leads to decreased APP transport towards the synapse and APP accumulation in the soma. The developed model thus couples three processes: (i) slow axonal transport of tau, (ii) tau misfolding and agglomeration, which we simulated by using the Finke-Watzky model and (iii) fast axonal transport of APP...
February 2018: Proceedings. Mathematical, Physical, and Engineering Sciences
Katalin Völgyi, Kata Badics, Fernando J Sialana, Péter Gulyássy, Edina Brigitta Udvari, Viktor Kis, László Drahos, Gert Lubec, Katalin Adrienna Kékesi, Gábor Juhász
Intracellular β-amyloid (Aβ) accumulation is an early event in Alzheimer's disease (AD) progression. Recently, it has been uncovered that presenilins (PSs), the key components of the amyloid precursor protein (APP) processing and the β-amyloid producing γ-secretase complex, are highly enriched in a special sub-compartment of the endoplasmic reticulum (ER) functionally connected to mitochondria, called mitochondria-associated ER membrane (MAM). A current hypothesis of pathogenesis of Alzheimer's diseases (AD) suggests that MAM is involved in the initial phase of AD...
February 22, 2018: Molecular Neurobiology
Alicia Delrivo, Carolina Aloisio, Marcela R Longhi, Gladys Granero
We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5 donor/pH 7.4 receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (Papp ) and the oral dose fraction absorbed in humans (fa ) of 16 drugs with different absorption properties. The Papp values correlated well with the absorption rates under the two conditions, and the method showed high predictability and good reproducibility...
April 2018: AAPS PharmSciTech
Papungkorn Sangsawad, Sittiruk Roytrakul, Kiattawee Choowongkomon, David D Kitts, Xiu-Min Chen, Guangtao Meng, Eunice C Y Li-Chan, Jirawat Yongsawatdigul
Korat-chicken breast and thigh were subjected to heating at 70, 100 or 121 °C for 30 min and simulated in vitro gastrointestinal digestion. At 70 or 100 °C heating, digests of breast possessed higher ACE inhibitory activity than those of thigh. The highest ACE inhibitory activity was found in the digest of breast cooked at 70 °C (B/H-70), whereas breast heated at 121 °C (B/H-121) exhibited the lowest. The 1-kDa permeate of the B/H-70 digest revealed higher permeability through colorectal adenocarcinoma monolayers and ACE inhibitory activity than did B/H-121...
June 15, 2018: Food Chemistry
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