Abstract：
:Alzheimer's disease (AD) is the most common neurodegenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound, L1 [4-(benzo[d]thiazol-2-yl)-2-((4,7-dimethyl-1,4,7-triazonan-1-yl)methyl)-6-methoxyphenol], that integrates Aβ-interacting and metal-binding fragments in a single molecular framework, exhibits significant antioxidant activity and metal chelating ability, and also rescues neuroblastoma N2A cells from Cu2+-induced Aβ neurotoxicity. Along with demonstrating in vivo Aβ-binding and favorable brain uptake properties, L1 treatment of transgenic 5xFAD mice significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40-50% versus the vehicle-treated 5xFAD mice. Moreover, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these multifunctional properties of L1 to attenuate the formation of amyloid plaques and associated p-tau aggregates while also reducing the microglia-mediated neuroinflammatory response are quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Cho HJ,Sharma AK,Zhang Y,Gross ML,Mirica LMdoi
10.1021/acschemneuro.0c00114subject
Has Abstractpub_date
2020-05-20 00:00:00pages
1471-1481issue
10issn
1948-7193journal_volume
11pub_type
杂志文章abstract：:Selective potentiators of glutamate response at metabotropic glutamate receptor subtype 5 (mGluR5) have exciting potential for the development of novel treatment strategies for schizophrenia. A total of 1,382 compounds with positive allosteric modulation (PAM) of the mGluR5 glutamate response were identified through h...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn9000389
更新日期：2010-04-21 00:00:00
abstract：:Many physiological pathways are involved in appetite, food intake, and the maintenance of energy homeostasis. In particular, neuropeptides within the central nervous system have been demonstrated to be critical signaling molecules for modulating appetite. Both anorexigenic (appetite-decreasing) and orexigenic (appetit...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.8b00151
更新日期：2018-06-20 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：:Vesicular acetylcholine transporter (VAChT) is a member of the major facilitator superfamily (MFS). It contains conserved sequence motifs originally defined in the bacterial multidrug resistance transporter family of the MFS. Motif C (GSLV(227) A(228)PPFGGIL) is located at the C-terminal end of transmembrane helix 5 (...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn900033s
更新日期：2010-05-19 00:00:00
abstract：:The abnormal aggregation of α-synuclein (α-Syn) is closely associated with Parkinson's disease. Different post-translational modifications of α-Syn have been identified and contribute distinctly in α-Syn aggregation and cytotoxicity. Recently, α-Syn was reported to be N-terminally acetylated in cells, yet the function...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00250
更新日期：2017-10-18 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：:Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent o...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.6b00334
更新日期：2017-04-19 00:00:00
abstract：:Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00512
更新日期：2018-06-20 00:00:00
abstract：:The l-enantiomer is the predominant type of amino acid in all living systems. However, d-amino acids, once thought to be "unnatural", have been found to be indigenous even in mammalian systems and increasingly appear to be functioning in essential biological and neurological roles. Both d- and l-amino acid levels in t...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.6b00398
更新日期：2017-06-21 00:00:00
abstract：:α-Synuclein (α-syn) is a 140-amino acid protein that plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. However, the molecular determinants that are responsible for triggering and/or propagating α-syn aggregation and toxicity remain poorly understood. Several studies have...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn200074d
更新日期：2011-11-16 00:00:00
abstract：:Interactions between superoxide dismutase-1 (SOD1) and lipid membranes might be directly involved in the toxicity and intercellular propagation of aggregated SOD1 in amyotrophic lateral sclerosis (ALS), but the chemical details of lipid-SOD1 interactions and their effects on SOD1 aggregation remain unclear. This paper...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00086
更新日期：2018-07-18 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：:Parkinson's disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of othe...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.6b00440
更新日期：2017-05-17 00:00:00
abstract：:No selective drugs exist, and we have been designing, synthesizing, and evaluating multitarget-directed ligands since the beginning of modern medicinal chemistry, without knowing it, most possibly. The challenge to discover the efficient Multi-Target Small Molecules (MTSMs) for Alzheimer's disease (AD) therapy implies...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.8b00069
更新日期：2018-03-21 00:00:00
abstract：:Responsive or smart contrast agents (SCAs) represent a promising direction for development of novel functional MRI (fMRI) methods for the eventual noninvasive assessment of brain function. In particular, SCAs that respond to Ca(2+) may allow tracking neuronal activity independent of brain vasculature, thus avoiding th...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500049n
更新日期：2014-05-21 00:00:00
abstract：:Central norepinephrine (NE) and dopamine (DA) are involved in a variety of physiological functions and behaviors. Accumulating evidence suggests that NE neurons originating from the locus coeruleus (LC) innervate DA neurons of the ventral tegmental area (VTA) and influence VTA-DA neural activity. However, the underlyi...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00078
更新日期：2017-09-20 00:00:00
abstract：:N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 and two GluN2 subunits. The four GluN2 subtypes (GluN2A-GluN2D) have distinct functional properties a...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00329
更新日期：2018-02-21 00:00:00
abstract：:Protein function depends on both protein structure and amino acid (aa) sequence. Here we show that modular features of both structure and function can be quantified economically from the aa sequences alone for the small (40,42 aa) plaque-forming (aggregative) amyloid beta fragments. Some edge and center features of th...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn5001793
更新日期：2015-05-20 00:00:00
abstract：:Amyloid beta (Aβ) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer's disease (AD). Among the various pathways of multifaceted toxicity exhibited by Aβ aggregates in neuronal cells, generation of reactive oxygen species (ROS) by Aβ-CuII complex and mitochondrial damage are p...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00033
更新日期：2018-06-20 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：:Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitoc...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00013
更新日期：2018-07-18 00:00:00
abstract：:The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transpo...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn300036b
更新日期：2012-05-16 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：:A series of bimodal metabotropic glutamate-receptor targeted MRI contrast agents has been developed and evaluated, based on established competitive metabotropic Glu receptor subtype 5 (mGluR5) antagonists. In order to directly visualize mGluR5 binding of these agents on the surface of live astrocytes, variations in th...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn400175m
更新日期：2014-02-19 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：:Human epidemiological and animal-model studies suggest that separate exposure to stress or serotonin-selective reuptake inhibitor (SSRI) antidepressants during pregnancy increases risks for neurodevelopmental disorders in offspring. Yet, little is known about the combined effects of maternal stress and SSRIs with rega...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00180
更新日期：2019-07-17 00:00:00
abstract：:Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00236
更新日期：2018-11-21 00:00:00
abstract：:Accumulating evidence suggested that soluble oligomeric β-amyloid protein (Aβ) exerts diverse roles in neuronal cell death, neuroinflammation, oxidative stress, and the eventual dementia associated with Alzheimer's disease (AD). Developing an agent with multiple properties may be a reasonable strategy for the treatmen...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.6b00091
更新日期：2016-04-20 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：:Several antidepressants increase adult hippocampal neurogenesis (ahNG) in rodents, primates, and, potentially, humans. This effect may at least partially account for their therapeutic activity. The availability of antidepressants whose mechanism of action involves different neurotransmitter receptors represents an opp...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00175
更新日期：2017-09-20 00:00:00
