Abstract：
:A hallmark of Alzheimer's disease (AD) is the formation of senile plaques comprised of the β-amyloid (Aβ) peptide. Aβ fibrillization is a complex nucleation-dependent process involving a variety of metastable intermediate aggregates and features the formation of inter- and intramolecular salt bridges involving lysine residues, K16 and K28. Cationic lysine residues also mediate protein-lipid interactions via association with anionic lipid headgroups. As several toxic mechanisms attributed to Aβ involve membrane interactions, the impact of acetylation on Aβ40 aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated Aβ40 were produced. With increasing acetylation, fibril and oligomer formation decreased, eventually completely arresting fibrillization. In the presence of total brain lipid extract (TBLE) vesicles, acetylation reduced the interaction of Aβ40 with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated Aβ promoted annular aggregates. Finally, toxicity associated with Aβ40 was reduced with increasing acetylation in a cell culture assay. These results suggest that in the absence of membranes that the cationic character of lysine plays a major role in fibril formation. However, acetylation promotes unique aggregation pathways in the presence of lipid membranes.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Pilkington AW 4th,Schupp J,Nyman M,Valentine SJ,Smith DM,Legleiter Jdoi
10.1021/acschemneuro.9b00483subject
Has Abstractpub_date
2020-01-15 00:00:00pages
146-161issue
2issn
1948-7193journal_volume
11pub_type
杂志文章abstract：:Aggregation of hyperphosphorylated tau is the hallmark of several tauopathies, including Alzheimer's disease (AD). Although the mechanism underlying tau-associated neuronal damage remains unclear, it is believed that tau hyperphosphorylation is one of the key features in disease progression. A recent study demonstrate...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.8b00632
更新日期：2019-01-16 00:00:00
abstract：:Amyloid-β (Aβ) is a peptide fragment that is prone to aggregate into large fibrils under physiological conditions. Many techniques have been developed to quickly monitor the transition from a primarily monomeric peptide into fibrils. Here we propose a novel method for both incubating and monitoring changes in Aβ aggre...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn300135n
更新日期：2012-11-21 00:00:00
abstract：:Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for the rapid identification and optimization of selective and general chemotypes for both kappa (κ) opioid receptor (KOR) activation and inhibition. In this program, we have developed potent antagonists (IC(50) < 120 nM) or ago...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn200128x
更新日期：2012-03-21 00:00:00
abstract：:Cognitive dysfunctions, including impaired attention, learning, memory, and problem solving, occur in psychiatric diseases, such as depression, and are a hallmark of aging. Altered GABAergic signaling is similarly reported across these conditions, but therapeutic approaches are limited by pan-receptor activities of be...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00148
更新日期：2019-05-15 00:00:00
abstract：:Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, α-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 ...
journal_title：ACS chemical neuroscience
pub_type： 信件
doi：10.1021/acschemneuro.7b00063
更新日期：2017-06-21 00:00:00
abstract：:Pharmaceutical companies assessing the nervous system effects of candidate therapeutics often use a behavioral assay in rodents that assesses the drug's subjective (internal stimulus) effects. Variants of this so-called "drug discrimination task" have also been widely used by basic scientist for more than 50 years to ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00018
更新日期：2015-03-18 00:00:00
abstract：:We recently found that tamoxifen suppresses l-glutamate transport activity of cultured astrocytes. Here, in an attempt to separate the l-glutamate transporter-inhibitory activity from the estrogen receptor-mediated genomic effects, we synthesized several compounds structurally related to tamoxifen. Among them, we iden...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn200091w
更新日期：2012-02-15 00:00:00
abstract：:The sensory nervous system controls cardiovascular homeostasis via capsaicin-sensitive neurons that release calcitonin gene-related peptide (CGRP), which subsequently activates CGRP receptors. How this perivascular CGRPergic discharge is modulated, nevertheless, remains unclear. In pithed rats, systemic vasodilation i...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00277
更新日期：2019-08-21 00:00:00
abstract：:The intramembrane aspartyl protease γ-secretase (GSEC) cleaves single-span transmembrane helices including the C-terminal fragment of the amyloid precursor protein (APP). This substrate is initially cleaved at the ϵ-site followed by successive processing (trimming) events mostly in steps of three amino acids. GSEC is ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00725
更新日期：2019-03-20 00:00:00
abstract：:The fibrillogenesis of amyloid-β protein (Aβ) is considered a crucial factor in the pathogenesis of Alzheimer's disease (AD). Hence, inhibiting Aβ fibrillogenesis is regarded as the primary therapeutic strategy for the prevention and treatment of AD. However, the development of effective inhibitors against Aβ fibrillo...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00441
更新日期：2019-01-16 00:00:00
abstract：:Large aggregates of misfolded α-synuclein inside neuronal cells are the hallmarks of Parkinson's disease. The protein's natural function and its supposed toxicity, however, are believed to be closely related to its interaction with cell and vesicle membranes. Upon this interaction, the protein folds into an α-helical ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn5002683
更新日期：2015-03-18 00:00:00
abstract：:We recently reported that AMP-activated protein kinase (AMPK) contributes to zinc-induced neuronal death by inducing Bim, a pro-apoptotic Bcl-2 homology domain 3-only protein, in a liver kinase B1 (LKB1)-dependent manner. Current data suggest AMPK plays key roles in excitotoxicity and ischemic brain injury, with zinc ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00654
更新日期：2019-05-15 00:00:00
abstract：:Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic sc...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.6b00125
更新日期：2016-11-16 00:00:00
abstract：:G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-d-glucoside (LysoPtdGlc)....
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00505
更新日期：2019-01-16 00:00:00
abstract：:Post-translational modifications of proteins are ubiquitous in living organisms, as they enable an accurate control of the interactions of these macromolecules. For mechanistic studies, it would be highly advantageous to be able to produce in vitro post-translationally modified proteins with site-specificity. Here, we...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00761
更新日期：2021-01-19 00:00:00
abstract：:Artesunate is a safe noncytotoxic drug with low side effects which is used in the treatment of chloroquine-resistant malaria. In addition to being an antimalarial drug, artesunate also has immunomodulatory, anticarcinogenic, and antiviral activity. There are in vivo and in vitro studies reporting that artesunate may h...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00601
更新日期：2020-12-16 00:00:00
abstract：:The nitrocatechol derivatives tolcapone (1) and entacapone (2), used as adjunctive therapy in the treatment of Parkinson's disease, were investigated for their potential to inhibit the tau-derived-hexapeptide 306VQIVYK311. They were compared to small molecules that contain similar pharmacophores including the catechol...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn400151a
更新日期：2013-12-18 00:00:00
abstract：:The molecular pathogenesis of Alzheimer's disease (AD) is complex and sparsely understood. The relationship between AD's amyloid β (Aβ) peptides and neuronal membranes is central to Aβ's cytotoxicity and is directly modulated by the composition of the lipid headgroups. Molecular studies of the insertion of model Aβ40 ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500277f
更新日期：2015-03-18 00:00:00
abstract：:Of the free-living amoebae (FLA) Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. are known to cause encephalitis. Coined with the term "brain-eating amoebae" (BEA), infection of the central nervous system with FLA has a high mortality rate. A combination of diagnostic delay, lack of new drug developm...
journal_title：ACS chemical neuroscience
pub_type： 社论
doi：10.1021/acschemneuro.9b00635
更新日期：2020-08-19 00:00:00
abstract：:The antioxidant activity of selenium, which is mainly conferred by its incorporation into dedicated selenoproteins, has been suggested as a possible neuroprotective approach for mitigating neuronal loss in Alzheimer's disease. However, there is inconsistent information with respect to selenium levels in the Alzheimer'...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00014
更新日期：2017-07-19 00:00:00
abstract：:Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote coca...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn300072u
更新日期：2013-01-16 00:00:00
abstract：:Aβ peptides, the main protein components of Alzheimer's disease (AD) plaques, derive from a proteolytic cleavage of the amyloid precursor protein. Due to heterogeneous cleavage sites, a series of Aβ peptides, including the major and widely studied species Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), are produced. In addition to t...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.6b00456
更新日期：2017-04-19 00:00:00
abstract：:MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn400077d
更新日期：2013-08-21 00:00:00
abstract：:Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble β-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, c...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00527
更新日期：2018-06-20 00:00:00
abstract：:Carboranes have been extensively investigated as potential drugs for the treatment of malignant human brain tumors by boron neutron capture therapy (BNCT). This noninvasive treatment modality utilizes compounds containing the nonradioactive isotope 10B which has a high propensity to capture slow neutrons. In response,...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00512
更新日期：2019-03-20 00:00:00
abstract：:Several lines of evidence suggest the presence of severe acute respiratory coronavirus-2 (SARS-CoV-2) in wastewater. The use of sewage water for irrigation is common in many developing countries, and it is only partially treated in the majority of countries with less than 10% of collected wastewater receiving any form...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00570
更新日期：2020-10-07 00:00:00
abstract：:This work describes the use of fluorescence correlation spectroscopy (FCS) and a novel amyloid-binding fluorescent probe, ARCAM 1, to monitor the aggregation of the Alzheimer's disease-associated amyloid β-peptide (Aβ). ARCAM 1 exhibits a large increase in fluorescence emission upon binding to Aβ assemblies, making it...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00176
更新日期：2015-09-16 00:00:00
abstract：:The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agon...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn100106a
更新日期：2011-05-18 00:00:00
abstract：:In this article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties o...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn400106n
更新日期：2013-10-16 00:00:00
abstract：:Extensive experimental and computational studies have suggested that multiple Zn(2+) binding modes in amyloid β (Aβ) peptides could exist simultaneously. However, consistent results have not been obtained for the effects of Zn(2+) binding on Aβ structure, dynamics, and kinetics in particular. Some key questions such a...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn4001445
更新日期：2013-11-20 00:00:00
