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Ahmed Elkamhawy, Jung-Eun Park, Ahmed H E Hassan, Ae Nim Pae, Jiyoun Lee, Sora Paik, Beoung-Geon Park, Eun Joo Roh
Herein, we report synthesis and evaluation of new twenty-eight pyrazinyl ureas against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea (5) effectively maintained mitochondrial function and cell viabilities on ATP assay and MTT assay...
July 31, 2018: European Journal of Medicinal Chemistry
Hannah Lowes, Angela Pyle, Martin Duddy, Gavin Hudson
Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS...
August 8, 2018: Mitochondrion
Igri Kolaj, S Imindu Liyanage, Donald F Weaver
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive dementia, neuroinflammation and the accumulation of intracellular neurofibrillary tangles and extracellular plaques. The etiology of AD is unclear, but is generally attributed to four leading hypotheses: (i) abnormal folding and aggregation of amyloid-β (Aβ)/tau proteins (ii) activation of the innate immune system, (iii) mitochondrial dysfunction, and (iv) oxidative stress. To date, therapeutic strategies have largely focused on Aβ-centric targets; however, the repeated failure of clinical trials and the continued lack of a disease-modifying therapy demand novel, multifaceted approaches...
August 8, 2018: Neurochemistry International
Omid Tavassoly, Dorin Sade, Santu Bera, Shira Shaham-Niv, David Vocadlo, Ehud Gazit
Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology. Mutations in genes encoding kynurenine pathway enzymes, that control the level of QA production, are linked with elevated risk of developing Parkinson's disease (PD). Recent findings have revealed the accumulation and deposition of QA in post-mortem samples, as well as in cellular models of Alzheimer's disease (AD) and related disorders...
August 8, 2018: Journal of Molecular Biology
Rosa Camila Lucchetta, Barbara Paes Miglioli da Mata, Patricia Carvalho Mastroianni
STUDY OBJECTIVE: Divergent opinions exist on the use of benzodiazepines and the development of dementia, with studies indicating that benzodiazepines could be either a protective factor or a risk factor for dementia, or that there may be an absence of an association between the two. The objective of this study was to identify whether an association exists between the use of benzodiazepines and the development of dementia. DESIGN: Systematic review and meta-analysis of 12 prospective and retrospective cohort studies and case-control studies...
August 11, 2018: Pharmacotherapy
Rachel Waller, Mark Murphy, Claire J Garwood, Luke Jennings, Paul R Heath, Annabelle Chambers, Fiona E Matthews, Carol Brayne, Paul G Ince, Stephen B Wharton, Julie E Simpson
Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and -II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2 O2 -modulation of MT transcription by human astrocytes...
August 10, 2018: Glia
Laurine Andre, Adeline Gallini, François Montastruc, Nicola Coley, Jean-Louis Montastruc, Bruno Vellas, Sandrine Andrieu, Virginie Gardette
AIM: To assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over 3 years. METHODS: We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score (Mini Mental State Examination orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test) at 12, 24 and 36 months...
August 10, 2018: British Journal of Clinical Pharmacology
Ben J Gu, James S Wiley
The P2X7 receptor (P2X7 or P2X7R) has been widely studied for ATP-induced proinflammation, but in the absence of ligand, P2X7 has a second function as a scavenger receptor which is active in the development of human brain. The scavenger activity of P2X7 is only evident in the absence of serum but is fully active in cerebrospinal fluid. P2X7 on the cell surface is present as a membrane complex and an attachment to nonmuscle myosin of the cytoskeleton is required for particle engulfment. Selective antagonists of P2X7 proinflammatory function have little effect on phagocytosis but coinheritance of a haplotype spanning in P2RX7 and P2RX4 genes has been associated with loss of P2X7 mediated phagocytosis...
August 10, 2018: British Journal of Pharmacology
Michael Rosenbloom, Terry R Barclay, Soo Borson, Ann M Werner, Lauren O Erickson, Jean M Crow, Kamakshi Lakshminarayan, Logan H Stuck, Leah R Hanson
BACKGROUND: Alzheimer's disease, the most common cause of dementia, goes unrecognized in half of patients presenting to healthcare providers and is associated with increased acute care utilization. Routine cognitive screening of older adults in healthcare settings could improve rates of dementia diagnosis and patterns of healthcare utilization. OBJECTIVE: To evaluate the impact of screening positive for cognitive impairment on provider action in primary and specialty care practices and patient healthcare utilization...
August 10, 2018: Journal of General Internal Medicine
In Jun Yeo, Mi Hee Park, Dong Ju Son, Ji Young Kim, Kyoung Tak Nam, Byung Kook Hyun, So Young Kim, Myung Hee Jung, Min Ji Song, Hyung Ok Chun, Tae Hyung Lee, Sang-Bae Han, Jin Tae Hong
Impaired neurogenesis has been associated with several brain disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The role of peroxiredoxin 6 (PRDX6) in neurodegenerative diseases is very controversial. To demonstrate the role of PRDX6 in neurogenesis, we compared the neurogenesis ability of PRDX6-overexpressing transgenic (Tg) mice and wild-type mice and studied the involved molecular mechanisms. We showed that the neurogenesis of neural stem cells (NSCs) and the expression of the marker protein were lower in PRDX6 Tg-mice than in wild-type mice...
August 10, 2018: Molecular Neurobiology
Khwaja Salahuddin Siddiqi, Azamal Husen, Sayed Sartaj Sohrab, Mensur Osman Yassin
Nanomaterials (NMs) are receiving remarkable attention due to their unique properties and structure. They vary from atoms and molecules along with those of bulk materials. They can be engineered to act as drug delivery vehicles to cross blood-brain barriers (BBBs) and utilized with better efficacy and safety to deliver specific molecules into targeted cells as compared to conventional system for neurological disorders. Depending on their properties, various metal chelators, gold nanoparticles (NPs), micelles, quantum dots, polymeric NPs, liposomes, solid lipid NPs, microparticles, carbon nanotubes, and fullerenes have been utilized for various purposes including the improvement of drug delivery system, treatment response assessment, diagnosis at early stage, and management of neurological disorder by using neuro-engineering...
August 10, 2018: Nanoscale Research Letters
Mi Eun Kim, Ju Yong Na, Yong-Duk Park, Jun Sik Lee
Microglia, resident macrophages of the central nervous system (CNS), is responsible for immune responses and homeostasis of the CNS. Microglia plays a complex role in neuroinflammation, which has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Therefore, therapeutic agents that suppress the microglia-mediated inflammatory response could potentially be used in the prevention or treatment of neurodegenerative diseases. Vanillin, a primary component of vanilla bean extract, has anti-inflammatory, anticancer, and antitumor properties...
August 10, 2018: Applied Biochemistry and Biotechnology
Tatiana Orme, Rita Guerreiro, Jose Bras
PURPOSE OF REVIEW: Dementia with Lewy bodies (DLB) is a neurodegenerative disease that can be clinically and pathologically similar to Parkinson's disease (PD) and Alzheimer's disease (AD). Current understanding of DLB genetics is insufficient and has been limited by sample size and difficulty in diagnosis. The first genome-wide association study (GWAS) in DLB was performed in 2017; a time at which the post-GWAS era has been reached in many diseases. RECENT FINDINGS: DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA...
August 10, 2018: Current Neurology and Neuroscience Reports
Jinping Cheng, Nils Korte, Ross Nortley, Huma Sethi, Yamei Tang, David Attwell
Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood-brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood-brain barrier, capillary blood flow and the movement of immune cells into the brain...
August 10, 2018: Acta Neuropathologica
Fiona H McLean, Christine Grant, Amanda C Morris, Graham W Horgan, Alex J Polanski, Kevin Allan, Fiona M Campbell, Rosamund F Langston, Lynda M Williams
Alzheimer's disease is a leading cause of morbidity and mortality with no cure and only limited treatment available. Obesity and type 2 diabetes are positively associated with the development of premature cognitive decline and Alzheimer's disease, linking diet with these conditions. Here we demonstrate that in mice episodic memory, together with spatial and contextual associative memory, is compromised after only one day of high-fat diet. However, object memory remains intact. This shows not only a more rapid effect than previously reported but also that more complex memories are at higher risk of being compromised by a high-fat diet...
August 10, 2018: Scientific Reports
Hiroto Kuwabara, Robert A Comley, Edilio Borroni, Michael Honer, Kelly Kitzmiller, Joshua Roberts, Lorena Gapasin, Anil Mathur, Gregory Klein, Dean F Wong
Rationale: The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand 18 F-RO-948 (previously referred to as 18 F-RO6958948) and its ability to identify tau-positivity in individual patients with mild Alzheimer's disease (AD). Methods: Eleven amyloid-positive, mild AD subjects, five amyloid-negative older (OC), and five younger (YC) control subjects completed one or two (4 AD and 5 OC) PET scans with 18 F-RO-948 for 90, 120, or 200 min...
August 10, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Roger B Dodd
Partial loss-of-function variants in the TREM2 immune receptor are associated with increased risk for Alzheimer's disease (AD) and other forms of neurodegenerative disease, but the molecular bases for these connections are unknown. Three new structures of WT and R47H mutant TREM2 immunoglobulin-like (Ig-like) domain now reveal that R47 functions to correctly position elements of the ligand-binding surface. Intriguingly, the authors also demonstrate a disruption of receptor oligomerization by the R47H mutation, suggesting a role for ligand-induced clustering in receptor signaling and resultant plaque clearance...
August 10, 2018: Journal of Biological Chemistry
Francisco Morales-Zavala, Nathalie Casanova-Morales, Raúl B Gonzalez, América Chandía-Cristi, Lisbell D Estrada, Ignacio Alvizú, Victor Waselowski, Fanny Guzman, Simón Guerrero, Marisol Oyarzún-Olave, Cristian Rebolledo, Enrique Rodriguez, Julien Armijo, Heman Bhuyan, Mario Favre, Alejandra R Alvarez, Marcelo J Kogan, Jerónimo R Maze
BACKGROUND: Stable and non-toxic fluorescent markers are gaining attention in molecular diagnostics as powerful tools for enabling long and reliable biological studies. Such markers should not only have a long half-life under several assay conditions showing no photo bleaching or blinking but also, they must allow for their conjugation or functionalization as a crucial step for numerous applications such as cellular tracking, biomarker detection and drug delivery. RESULTS: We report the functionalization of stable fluorescent markers based on nanodiamonds (NDs) with a bifunctional peptide...
August 10, 2018: Journal of Nanobiotechnology
Yi-Heng Lee, Hao-Chieh Hsu, Pei-Chen Kao, Young-Ji Shiao, Skye Hsin-Hsien Yeh, Feng-Shiun Shie, Shu-Meng Hsu, Chih-Wen Yeh, Hui-Kang Liu, Shi-Bing Yang, Huey-Jen Tsay
Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD...
August 8, 2018: International Journal of Molecular Sciences
Yu-Chia Kao, I-Fang Wang, Kuen-Jer Tsai
Microribonucleic acids (miRNAs) play a pivotal role in numerous aspects of the nervous system and are increasingly recognized as key regulators in neurodegenerative diseases. This study hypothesized that miR-34c, a miRNA expressed in mammalian hippocampi whose expression level can alter the hippocampal dendritic spine density, could induce memory impairment akin to that of patients with Alzheimer's disease (AD) in mice. In this study, we showed that miR-34c overexpression in hippocampal neurons negatively regulated dendritic length and spine density...
August 8, 2018: International Journal of Molecular Sciences
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