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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
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...
November 4, 2016: Life Sciences
Balmiki Ray, Deborah K Sokol, Bryan Maloney, Debomoy K Lahiri
UNLABELLED: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-β (Aβ) precursor protein (APP) and metabolites are usually associated with Alzheimer's disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. β-site APP cleaving enzyme (BACE1) cleavage produces secreted APPβ (sAPPβ) and intact Aβ...
May 23, 2016: Scientific Reports
Stephanie Plummer, Corinna Van den Heuvel, Emma Thornton, Frances Corrigan, Roberto Cappai
Despite the significant health and economic burden that traumatic brain injury (TBI) places on society, the development of successful therapeutic agents have to date not translated into efficacious therapies in human clinical trials. Injury to the brain is ongoing after TBI, through a complex cascade of primary and secondary injury events, providing a valuable window of opportunity to help limit and prevent some of the severe consequences with a timely treatment. Of note, it has been suggested that novel treatments for TBI should be multifactorial in nature, mimicking the body's own endogenous repair response...
March 2016: Aging and Disease
Bob Olsson, Ronald Lautner, Ulf Andreasson, Annika Öhrfelt, Erik Portelius, Maria Bjerke, Mikko Hölttä, Christoffer Rosén, Caroline Olsson, Gabrielle Strobel, Elizabeth Wu, Kelly Dakin, Max Petzold, Kaj Blennow, Henrik Zetterberg
BACKGROUND: Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease...
June 2016: Lancet Neurology
Peng Guo, Desheng Wang, Xiaomin Wang, Honglin Feng, Ying Tang, Ruihong Sun, Yan Zheng, Lin Dong, Jiaying Zhao, Xin Zhang, Shuyu Wang, Hongxu Sun
The present study aimed to determine the effect and mechanism of fuzhisan (FZS) and donepezil on the SIRT1 signaling pathway and the metabolism of the amyloid precursor protein (APP) in PC12 cells. An experimental cell model of PC12 cells with Aβ25‑35‑induced neurotoxicity was established and cell proliferation was determined by the MTT assay following treatment with donepezil and FZS. In addition, cell apoptosis was determined using DAPI staining and light microscopy. Furthermore, western blot analysis and ELISA were utilized to evaluate the expression levels of associated APP, Aβ40, Aβ42, sAPPα, sAPPβ, ADAM10, sirtuin 1 (SIRT1) and forkhead box O (FoxO) protein...
April 2016: Molecular Medicine Reports
Caroline Schönherr, Jessica Bien, Simone Isbert, Rielana Wichert, Johannes Prox, Hermann Altmeppen, Sathish Kumar, Jochen Walter, Stefan F Lichtenthaler, Sascha Weggen, Markus Glatzel, Christoph Becker-Pauly, Claus U Pietrzik
BACKGROUND: The metalloprotease meprin β cleaves the Alzheimer's Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants. RESULTS: Herein, we observed increased endogenous sAPPα levels in the brains of meprin β knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis...
2016: Molecular Neurodegeneration
Mei-Chen Liao, Christina R Muratore, Todd M Gierahn, Sarah E Sullivan, Priya Srikanth, Philip L De Jager, J Christopher Love, Tracy L Young-Pearse
UNLABELLED: Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance...
February 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Eline M T van Maanen, Tamara J van Steeg, Maria S Michener, Mary J Savage, Matthew E Kennedy, Huub Jan Kleijn, Julie A Stone, Meindert Danhof
The deposition of amyloid-β (Aβ) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the β-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aβ42, Aβ40, soluble β-amyloid precursor protein (sAPP) α, and sAPPβ in CSF...
April 2016: Journal of Pharmacology and Experimental Therapeutics
Linda J C van Waalwijk van Doorn, Marleen J Koel-Simmelink, Ute Haußmann, Hans Klafki, Hanne Struyfs, Philipp Linning, Hans-Joachim Knölker, Harry Twaalfhoven, H Bea Kuiperij, Sebastiaan Engelborghs, Philip Scheltens, Marcel M Verbeek, Eugeen Vanmechelen, Jens Wiltfang, Charlotte E Teunissen
Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPα and sAPPβ ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism...
April 2016: Journal of Neurochemistry
Tongrong He, Anantha Vijay R Santhanam, Tong Lu, Livius V d'Uscio, Zvonimir S Katusic
We tested hypothesis that activation of the prostacyclin (PGI2) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI2, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα)...
November 20, 2015: Journal of Cerebral Blood Flow and Metabolism
R G J Gonçalves, J F Vasques, P Trindade, C A Serfaty, P Campello-Costa, A C Faria-Melibeu
During early postnatal development retinocollicular projections undergo activity-dependent synaptic refinement that results in the formation of precise topographical maps in the visual layers of the superior colliculus (SC). Amyloid Precursor Protein (APP) is a widely expressed transmembrane glycoprotein involved in the regulation of several aspects of neural development, such as neurite outgrowth, synapse formation and plasticity. Stimulation of cholinergic system has been found to alter the expression and processing of APP in different cell lines...
January 28, 2016: Neuroscience
Arpita Kundu, Nelli Milosch, Patrick Antonietti, Frederik Baumkötter, Andreas Zymny, Ulrike C Müller, Stefan Kins, Parvana Hajieva, Christian Behl, Donat Kögel
Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease (AD). sAPPalpha (sAPPα), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPα directly affects proteostasis...
November 2, 2015: Molecular Neurobiology
Wei Huang, Lirong Zhou, Xiaoou Li, Hongxia Sun, Ting Zhou, Xiaogang Huang, Qiao Liu
OBJECTIVE: To construct and express a single chain fragment of variety region (scFv) against β-site of amyloid precursor protein (APP), and evaluate the effect of scFv on α- and β-processing of APP. METHODS: The β-site specific scFv 2H10 was amplified and fused with signal sequence Igκ and myc tag by PCR to create the expression cassette, which was then subcloned into expression vector pcDNA3.1hyg⁺. The plasmid was transferred into CHO cells over-expressing Swedish mutation type human APP695 (APP695sw/CHO)...
October 2015: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Juan Deng, Ahsan Habib, Demian F Obregon, Steven W Barger, Brian Giunta, Yan-Jiang Wang, Huayan Hou, Darrell Sawmiller, Jun Tan
We recently found that sAPPα decreases amyloid-beta generation by directly associating with β-site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3β)-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPPα also reduces GSK3β-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over-expressing mice...
November 2015: Journal of Neurochemistry
L Devi, M Ohno
β-Site APP-cleaving enzyme 1 (BACE1) initiates the generation of amyloid-β (Aβ), thus representing a prime therapeutic target for Alzheimer's disease (AD). Previous work including ours has used BACE1 haploinsufficiency (BACE1(+/-); i.e., 50% reduction) as a therapeutic relevant model to evaluate the efficacy of partial β-secretase inhibition. However, it is unclear whether the extent of Aβ reductions in amyloid precursor protein (APP) transgenic mice with BACE1(+/-) gene ablation may vary with sex or disease progression...
October 29, 2015: Neuroscience
Donna Darlington, Song Li, Huayan Hou, Ahsan Habib, Jun Tian, Yang Gao, Jared Ehrhart, Paul R Sanberg, Darrell Sawmiller, Brian Giunta, Takashi Mori, Jun Tan
Alzheimer's disease (AD) is the fourth major cause of mortality in the elderly in the US and the leading cause of dementia worldwide. While pharmacological targets have been discovered, there are no true disease-modifying therapies. We have recently discovered that multiple low-dose infusions of human umbilical cord blood cells (HUCBCs) ameliorate cognitive impairments and reduce Aβ-associated neuropathology in PSAPP transgenic mice. However, the mechanism for these effects of HUCBCs remains unclear. In the present study, we examined whether monocytes, as important components of HUCBCs, would have beneficial outcomes on the reduction of AD-like pathology and associated cognitive impairments in PSAPP transgenic AD model mice...
2015: Cell Transplantation
Emanuela Pasciuto, Tariq Ahmed, Tina Wahle, Fabrizio Gardoni, Laura D'Andrea, Laura Pacini, Sébastien Jacquemont, Flora Tassone, Detlef Balschun, Carlos G Dotti, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, Ulrike C Müller, Monica Di Luca, Bart De Strooper, Claudia Bagni
The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits...
July 15, 2015: Neuron
Signar Mäkitalo, Åsa Mellgren, Ellen Borgh, Lena Kilander, Tobias Skillbäck, Henrik Zetterberg, Magnus Gisslén
It is a challenge to differentiate between HIV-associated neurocognitive disorders (HAND) and other types of neurocognitive disease in the ageing HIV-infected population. Here we describe a 63 year old HIV-infected woman who had a history, neuropsychological test result, and PET examination consistent with characteristic Alzheimer's disease (AD). The cerebrospinal fluid (CSF) biomarker profile was analogous to the profile typically found in AD in HIV-negative patients with increased t-tau and p-tau, a decreased level of Aβ42 and normal levels of CSF neurofilament light protein and sAPPα and sAPPβ, distinctly different from findings in HIV-associated dementia (HAD)...
2015: AIDS Research and Therapy
Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Chihiro Akiba, Hidenori Sugano, Takeshi Hara, Keiko Fusegi, Kostadin Karagiozov, Hajime Arai
The prognosis of cognitive improvement after cerebrospinal fluid (CSF) shunting in idiopathic normal pressure hydrocephalus (iNPH) remains uncertain, with no reports on CSF biomarkers related to long-term cognitive prognosis. We performed a preliminary study of CSF biomarker protein levels for cognitive outcome prognostication of two-year outcomes after shunt treated iNPH in 36 patients (13 women) with a median age of 75years (IQR 69-78). CSF biomarkers included soluble amyloid precursor proteins (sAPP, sAPPα, sAPPβ), amyloid β (Aβ)1-38, Aβ1-42 and phosphorylated tau (p-tau), lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace, and cystatin C...
October 15, 2015: Journal of the Neurological Sciences
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