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David J Koss, Glynn Jones, Anna Cranston, Heidi Gardner, Nicholas M Kanaan, Bettina Platt
Post-mortem investigations of human Alzheimer's disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of β-amyloid (Aβ) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Aβ plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Aβ species has more recently been implicated as the disease-relevant toxic entities...
October 21, 2016: Acta Neuropathologica
Maria Gregori, Mark Taylor, Elisa Salvati, Francesca Re, Simona Mancini, Claudia Balducci, Gianluigi Forloni, Vanessa Zambelli, Silvia Sesana, Maria Michael, Christos Michail, Claire Tinker-Mill, Oleg Kolosov, Michael Scherer, Stephen Harris, Nigel J Fullwood, Massimo Masserini, David Allsop
Aggregation of Amyloid-β peptide (Aβ) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ...
October 18, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Christopher D Morrone, Lynsie A M Thomason, Mary E Brown, Isabelle Aubert, JoAnne McLaurin
Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer's disease (AD)-like pathology, specifically Aβ-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aβ pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment...
2016: PloS One
Qian Cai, Prasad Tammineni
Alzheimer's disease (AD) is characterized by brain deposition of amyloid plaques and tau neurofibrillary tangles along with steady cognitive decline. Synaptic damage, an early pathological event, correlates strongly with cognitive deficits and memory loss. Mitochondria are essential organelles for synaptic function. Neurons utilize specialized mechanisms to drive mitochondrial trafficking to synapses in which mitochondria buffer Ca2+ and serve as local energy sources by supplying ATP to sustain neurotransmitter release...
October 20, 2016: Journal of Alzheimer's Disease: JAD
Gvido Cebers, Robert C Alexander, Samantha Budd Haeberlein, David Han, Ronald Goldwater, Larry Ereshefsky, Tina Olsson, Naidong Ye, Laura Rosen, Muir Russell, Justine Maltby, Susanna Eketjäll, Alan R Kugler
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16)...
October 19, 2016: Journal of Alzheimer's Disease: JAD
Maria Anderson, Feng Xu, Ming-Hsuan Ou-Yang, Judianne Davis, William E Van Nostrand, John K Robinson
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field...
October 19, 2016: Journal of Alzheimer's Disease: JAD
Peter Nilsson, Marcus Bäck, Hanna Appelqvist, Harry LeVine
Deposits comprised of amyloid-β(Aβ) are one of the pathological hallmarks of Alzheimer's disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Aβ amyloid fibrils and Alzheimer's disease brain-derived Aβ. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for Aβ pathology only found in human AD brain, targeting a different site than PIB...
October 21, 2016: Chemistry: a European Journal
Natarajan Suganthy, Dicson Sheeja Malar, Kasi Pandima Devi
OBJECTIVE: Amyloid hypothesis states that endogenous β-amyloid peptides (Aβ), especially its aggregated oligomers and fibrils are the key pathogenic factors leading to Alzheimer's disease (AD). Therefore, inhibition of Aβ fibrillation rather than blocking its production is considered promising therapeutic intervention. Hence, the present study was carried out to assess the effect of methanolic leaf extract of R. mucronata (MERM) and its bioactive compound catechin on in vitro fibrillation of Aβ (25-35)...
October 21, 2016: Neurological Research
Hossein Derakhshankhah, Mohammad Javad Hajipour, Ebrahim Barzegari, Alireza Lotfabadi, Maryam Ferdousi, Ali Akbar Saboury, Eng-Poh Ng, Mohammad Raoufi, Hussein Awala, Svetlana Mintova, Rassoul Dinarvand, Morteza Mahmoudi
EMT-type zeolite nanoparticles (EMT NPs) with diameter smaller than 12 nm and uniform pore size of 7.3 Å have shown high selective affinity toward plasma protein (fibrinogen). Besides, the EMT NPs have demonstrated no adverse effect on blood coagulation hemostasis. Therefore, it was envisioned that the EMT NPs could inhibit possible β-Amyloid (Aβ)-fibrinogen interactions that result in the formation of structurally abnormal clots, which are resistant to lysis, in cerebral vessels of patients with Alzheimer disease (AD)...
October 21, 2016: ACS Applied Materials & Interfaces
Cinzia Guzzi, Laura Colombo, Ada De Luigi, Mario Salmona, Francesco Nicotra, Cristina Airoldi
Combining NMR spectroscopy, transmission electron microscopy, biochemical and in vitro toxicity assays, we characterized the effect of flavonoid glycosylation, a chemical modification very frequent in Nature, on their ability to recognise and bind Aβ1-42 oligomers, preventing their aggregation and their neurotoxicity. Our data allow the elucidation of their structure activity relationships, showing that glycosylation has a modest impact on flavonoid affinity for Aβ oligomers but, at the same time, increases both solubility and chemical stability, thus promoting their beneficial properties against Alzheimer's diseases (AD)...
October 21, 2016: Chemistry, An Asian Journal
Mythily Srinivasan, Baindu Bayon, Nipun Chopra, Debomoy K Lahiri
In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer's disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration...
2016: PloS One
Jian Yang, Jing Yang, Steven H Liang, Yungen Xu, Anna Moore, Chongzhao Ran
In brains of Alzheimer's disease (AD), reactive oxygen species (ROS) levels are significantly higher than that of healthy brains. Evidence suggests that, during AD onset and progression, a vicious cycle revolves around amyloid beta (Aβ) production, aggregation, plaque formation, microglia/immunological responses, inflammation, and ROS production. In this cycle, ROS species play a central role, and H2O2 is one of the most important ROS species. In this report, we have designed a fluorescent imaging probe CRANAD-88, which is capable of cascade amplifying near infrared fluorescence (NIRF) signals at three levels upon interacting with H2O2 in AD brains...
October 20, 2016: Scientific Reports
FangFang, Hongyan Li, Tingting Qin, Min Li, Shiping Ma
The impaired insulin signaling has been recognized as a common pathogenetic mechanism between diabetes and Alzheimer's disease (AD). In the progression of AD, brain is characterized by defective insulin receptor substrate-1 (IRS-1) and increased oxidative stress. Thymol, a monoterpene phenol isolated from medicinal herbs, has exhibited robust neuroprotective effects. The present study was designed to investigate the protective effect of thymol on HFD-induced cognitive deficits, and explore the possible mechanisms...
October 20, 2016: Metabolic Brain Disease
Moran Frenkel-Pinter, Sharon Tal, Roni Scherzer-Attali, Malak Abu-Hussien, Idan Alyagor, Tal Eisenbaum, Ehud Gazit, Daniel Segal
Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by Aβ-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered β-sheet oligomers and fibrils. Intervening in the toxic aggregation process is a promising therapeutic approach, but, to date, a disease-modifying therapy is neither available for AD nor for other tauopathies. Along these lines, we have previously demonstrated that a small naphthoquinone-tryptophan hybrid, termed NQTrp, is an effective modulator of tauopathy in vitro and in vivo...
October 20, 2016: Neuro-degenerative Diseases
Lara Ordóñez-Gutiérrez, Adrián Posado-Fernández, Davoud Ahmadvand, Barbara Lettiero, Linping Wu, Marta Antón, Orfeu Flores, Seyed Moein Moghimi, Francisco Wandosell
The accumulation of extracellular amyloid-beta (Aβ) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Aβ deposition and/or accelerate its clearance. With the aid of a newly characterized monoclonal anti-Aβ antibody we constructed immunoPEGliposomes with high avidity for capturing Aβ in the periphery. The functionality of these vesicles in modulating Aβ uptake by both human brain capillary endothelial hCMEC/D3 cells (suppressing uptake) and THP-1 phagocytes (stimulating uptake) was confirmed in vitro...
August 2, 2016: Biomaterials
Rosario Gajardo-Gómez, Valeria C Labra, Carola J Maturana, Kenji F Shoji, Cristian A Santibañez, Juan C Sáez, Christian Giaume, Juan A Orellana
The mechanisms involved in Alzheimer's disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated. Previous studies have shown that amyloid-β peptide (Aβ) induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglial hemichannel opening. We have demonstrated that synthetic and endogenous cannabinoids (CBs) reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators...
October 19, 2016: Glia
Rosalia Pellitteri, Roberta Bonfanti, Michela Spatuzza, Maria Teresa Cambria, Mariacristina Ferrara, Giuseppina Raciti, Agata Campisi
Herein, we assessed in a particular glial cell type, called olfactory ensheathing cells (OECs), the effect of some growth factors (GFs) on tissue transglutaminase (TG2) overexpression induced by amyloid-beta (Aβ) with native full-length peptide 1-42 or by fragments, 25-35 or 35-25, as control. Previously, we demonstrated that TG2 overexpression induced by some stressors was down-regulated by GFs exposure in OECs. To monitor cell viability, an MTT test was used, while TG2 expression was examined using immunocytochemical and Western blot analysis...
October 18, 2016: Molecular Neurobiology
Eric D Hamlett, Edward J Goetzl, Aurélie Ledreux, Vitaly Vasilevko, Heather A Boger, Angela LaRosa, David Clark, Steven L Carroll, Maria Carmona Iragui, Juan Fortea, Elliott J Mufson, Marwan Sabbagh, Abdul H Mohammed, Dean Hartley, Eric Doran, Ira T Lott, Ann-Charlotte Granholm
INTRODUCTION: Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid-β (Aβ) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. METHODS: AD neuropathogenic proteins Aβ1-42, P-T181-tau, and P-S396-tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls...
October 15, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Anna M Pietroboni, Francesca Schiano di Cola, Marta Scarioni, Chiara Fenoglio, Barbara Spanò, Andrea Arighi, Sara Mg Cioffi, Emanuela Oldoni, Milena A De Riz, Paola Basilico, Alberto Calvi, Giorgio G Fumagalli, Fabio Triulzi, Daniela Galimberti, Marco Bozzali, Elio Scarpini
BACKGROUND: Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression. OBJECTIVES: To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures...
October 17, 2016: Multiple Sclerosis: Clinical and Laboratory Research
Tengfei Guo, Matthias Brendel, Timo Grimmer, Axel Rominger, Igor Yakushev
: Knowledge about spatial and temporal patterns of beta-amyloid (Aβ) accumulation is essential for understanding Alzheimer's disease (AD) and for design of anti-amyloid drug trials. Here, we tested if the regional pattern of longitudinal Aβ accumulation can be predicted by baseline amyloid PET. METHODS: Analyzed were baseline and 2 years follow-up (18)F-florbetapir PET data from 58 patients with incipient and manifest dementia due to Alzheimer's disease (AD). By determining how fast amyloid deposits in a given region relative to the whole brain grey matter, a pseudo-temporal accumulation rate for each region was calculated...
October 6, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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