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picomolar amyloid memory

Xueying Wang, Ksenia V Kastanenka, Michal Arbel-Ornath, Caitlin Commins, Akira Kuzuya, Amanda J Lariviere, Grant A Krafft, Franz Hefti, Jasna Jerecic, Brian J Bacskai
Soluble amyloid β oligomers (AβOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer's disease (AD). One of the profound downstream consequences of AβO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+ ]i ), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AβO-blocking candidates by measuring AβO-induced real-time changes in [Ca2+ ]i ...
March 15, 2018: Scientific Reports
Hoau-Yan Wang, Kuo-Chieh Lee, Zhe Pei, Amber Khan, Kalindi Bakshi, Lindsay H Burns
We show that amyloid-β1-42 (Aβ42 ) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with α7-nicotinic acetylcholine receptor (α7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Aβ42 's toxic signaling via α7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its α7nAChR/TLR4 associations and downstream pathologies...
July 2017: Neurobiology of Aging
J V Bukanova, I N Sharonova, V G Skrebitsky
Amyloid-β peptide (Aβ) is considered a key protein in the pathogenesis of Alzheimer's disease because of its neurotoxicity, resulting in impaired synaptic function and memory. On the other hand, it was demonstrated that low (picomolar) concentrations of Aβ enhance synaptic plasticity and memory, suggesting that in the healthy brain, physiological Aβ concentrations are necessary for normal cognitive functions. In the present study, we found that Aβ (1-42) in concentrations of 10 pМ - 100nМ enhanced desensitization of the glycine-activated current in isolated CA3 pyramidal neurons and also reversibly suppressed its peak amplitude during short (600ms) co-application with agonist...
November 15, 2016: Brain Research
Peter Koppensteiner, Fabrizio Trinchese, Mauro Fà, Daniela Puzzo, Walter Gulisano, Shijun Yan, Arthur Poussin, Shumin Liu, Ian Orozco, Elena Dale, Andrew F Teich, Agostino Palmeri, Ipe Ninan, Stefan Boehm, Ottavio Arancio
The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer's disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it...
2016: Scientific Reports
John E Morley, Susan A Farr
In this review there is evidence that amyloid-beta peptide is a memory enhancer at physiological (picomolar) concentrations. Pathological overproduction of amyloid-beta leads to impaired memory, oxidative damage, damage to the blood brain barrier, neurofibrillary tangles and amyloid plaque formation. Antisenses to amyloid precursor protein (APP) can reverse these effects in mice when they lower amyloid-beta protein to physiological levels. Data suggests that overproduction of APP leads to oxidative stress producing a vicious cycle of neuronal damage...
April 15, 2014: Biochemical Pharmacology
Murat Oz, Dietrich E Lorke, Keun-Hang S Yang, Georg Petroianu
Deterioration of the cortical cholinergic system is a leading neurochemical feature of Alzheimer's Disease (AD). This review summarizes evidence that the homomeric α7- nicotinic acetylcholine receptor (nAChR) plays a crucial role in the pathogenesis of this disease, which is characterized by amyloid-β (Aβ) accumulations and neurofibrillary tangles originating from of hyperphosphorylated tau protein. Aβ binds to α7-nAChRs with a high affinity, either activating or inhibiting this receptor in a concentration-dependent manner...
July 2013: Current Alzheimer Research
Daniela Puzzo, Ottavio Arancio
Amyloid-β peptide (Aβ) is considered a key protein in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. Aβ derives from amyloid-β protein precursor (AβPP), whose proteolytic processing generates several fragments including Aβ peptides of various lengths. The normal function of AβPP and its fragments remains poorly understood. While some fragments have been suggested to have a function in normal physiological cellular processes, Aβ has been widely considered as a "garbage" fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory...
2013: Journal of Alzheimer's Disease: JAD
Alex L Lublin, Sam Gandy
Alzheimer's disease is the most common form of senile dementia. Although the amyloid-beta peptide was identified in 1984 as the major constituent of the senile plaques that characterize the disease, accumulating evidence indicates that the plaque density does not correspond well to the concurrent disease state. In order to resolve this disconnect, a number of recent studies have shifted away from the senile plaque and classical fibrillar forms of amyloid toward a less well structured species as the proximate neurotoxic factor underlying cognitive failure in Alzheimer's disease: soluble amyloid-beta peptide oligomer (also known as the amyloid-beta peptide-derived diffusible ligand)...
January 2010: Mount Sinai Journal of Medicine, New York
Ana Garcia-Osta, Cristina M Alberini
The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid beta (1-42) peptide (Abeta[1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated, endogenous Abeta in normal hippocampi mediates learning and memory formation. Furthermore, hippocampal injection of picomolar concentrations of exogenous Abeta(1-42) enhances memory consolidation...
April 2009: Learning & Memory
Daniela Puzzo, Lucia Privitera, Elena Leznik, Mauro Fà, Agnieszka Staniszewski, Agostino Palmeri, Ottavio Arancio
Amyloid-beta (Abeta) peptides are produced in high amounts during Alzheimer's disease, causing synaptic and memory dysfunction. However, they are also released in lower amounts in normal brains throughout life during synaptic activity. Here we show that low picomolar concentrations of a preparation containing both Abeta(42) monomers and oligomers cause a marked increase of hippocampal long-term potentiation, whereas high nanomolar concentrations lead to the well established reduction of potentiation. Picomolar levels of Abeta(42) also produce a pronounced enhancement of both reference and contextual fear memory...
December 31, 2008: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dennis J Selkoe
During the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid beta-protein (Abeta) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Abeta42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Abeta during some kinds of synaptic activity...
September 1, 2008: Behavioural Brain Research
Ling Chen, Kiyofumi Yamada, Toshitaka Nabeshima, Masahiro Sokabe
Continuous intracerebroventricular infusion of beta-amyloid peptide 1-40 (Abeta(1-40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. Beta-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from Abeta-infused brain...
February 2006: Neuropharmacology
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