Abstract:
BACKGROUND:Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD). OBJECTIVE:To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHODS:Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid β (Aβ) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aβ species, and the effects of compound 2 on apoptotic cascade. RESULTS:Compounds 2-4 competitively inhibited cathepsin B β-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aβ aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 μM. Compound 2 exerted neuroprotective effects towards Aβ toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aβ1-42. CONCLUSION:Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.
journal_name
Curr Alzheimer Resjournal_title
Current Alzheimer researchauthors
Knez D,Sosič I,Pišlar A,Mitrović A,Jukič M,Kos J,Gobec Sdoi
10.2174/1567205016666191010130351subject
Has Abstractpub_date
2019-01-01 00:00:00pages
801-814issue
9eissn
1567-2050issn
1875-5828pii
CAR-EPUB-101329journal_volume
16pub_type
杂志文章abstract::Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720501301151207100616
更新日期:2016-01-01 00:00:00
abstract::Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss a...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205016666190321163438
更新日期:2019-01-01 00:00:00
abstract::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) accumulatio...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/15672050113109990132
更新日期:2013-07-01 00:00:00
abstract::The aetiology of major neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is still unknown, but increasing evidences suggest that glutamate and mitochondria are two prominent players in the oxidative stress (OS) process that underlie these illnesses. Although AD and PD have distin...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205013666151218132725
更新日期:2016-01-01 00:00:00
abstract::Metabolic syndrome (MetS), i.e., meeting criteria for any three of the following: hyperglycemia, hypertension, hypertriglyceridemia, low high-density lipoprotein and/or abdominal obesity, is associated with negative health outcomes. For example, MetS negatively impacts cognition; however, less is known about increment...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205012666150701102325
更新日期:2015-01-01 00:00:00
abstract::Mild cognitive impairment (MCI) is a nosological entity associated with a higher risk of developing dementia. Previous evidence indicates that behavioral and psychological symptoms of dementia (BPSDs) frequently occur in individuals of MCI. These neuropsychiatric manifestations may predict conversion to dementia. Howe...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205013666160502123129
更新日期:2016-01-01 00:00:00
abstract::Alzheimer's disease (AD) is a progressive degenerative disorder of the brain and is the most common form of dementia. To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. T...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205011666140618103827
更新日期:2014-01-01 00:00:00
abstract::Soluble amyloid beta (Abeta) oligomers might trigger early cognitive impairment in Alzheimer's Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Abeta(25-35) affects the spontaneous activity in hippocampal slices, when was added to the bath, at high...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/156720510791383859
更新日期:2010-08-01 00:00:00
abstract::Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. In addition, it was implicated in amyloid plaque formation, a hallmark of Alzheimer's disease (AD), and most of the drugs used in AD treatment are ACh...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205053585909
更新日期:2005-04-01 00:00:00
abstract::The marginal division (MrD) is a neostriatum subregion that links the limbic system and basal nucleus of Meynert; it is an important subcortical center that is involved in learning and memory. Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the elderly. AD clinically m...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205011666140110112608
更新日期:2014-02-01 00:00:00
abstract::When Alzheimer's disease (AD) progresses, several pathological features arise including accumulation of misfolded protein aggregates [e.g., amyloid-β (Aβ) plaques], metal ion dyshomeostasis, and oxidative stress. These characteristics are recently suggested to be interconnected through a potential factor, metal-associ...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205012666150504150125
更新日期:2015-01-01 00:00:00
abstract::Apoptosis has been postulated to play a possible causal role in the onset of Alzheimer's disease due to shortage of trophic supply, deafferentation and excessive production of free radicals. Many experiments in the past have demonstrated the requirement of de novo gene expression during neuronal apoptosis. In view of ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720506778249416
更新日期:2006-09-01 00:00:00
abstract:OBJECTIVES:REM sleep behavior disorder (RBD), with its main clinical symptoms of nightmares with dream-enacting behavior, is considered as a possible precursor of neurodegenerative disease. Obstructive Sleep Apnea Syndrome (OSAS) is known to be capable of provoking RBD-like symptoms by apneic event related arousals. Th...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205014666170523094938
更新日期:2017-01-01 00:00:00
abstract::Amyloid beta peptide (Abeta), 42-residue peptide and its variations, is known to form amyloid fibrils in Alzheimer's disease. Solid-state NMR study reveals a parallel beta-sheet structure in the Abeta fibrils. The atomic level structure of Abeta in aqueous environment, however, has not been determined, because of its ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720508786898424
更新日期:2008-12-01 00:00:00
abstract::Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A characteristic of AD is the accumulation of plaques in the brain of AD patients, and theses plaques mainly consist of aggregates of amyloid beta-peptide (Abeta). All converging lines of evidence sugg...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720508784533321
更新日期:2008-06-01 00:00:00
abstract::Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH level...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205012666150302160308
更新日期:2015-01-01 00:00:00
abstract::In this review, the basic mechanism of the parasympathetic nervous effect on the heart is discussed. This is expanded to clinical situations to clarify what can happen to patients after cholinesterase (ChE) inhibitor is administered and to avoid unnecessary adverse effects. The parasympathetic nervous system can affec...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205043332009
更新日期:2004-11-01 00:00:00
abstract:BACKGROUND:Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to det...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205011666141001120903
更新日期:2014-01-01 00:00:00
abstract::Memory loss is a prominent health concern, second only to heart disease for older individuals. Docosahexaenoic acid (DHA), the principle omega-3 fatty acid in brain and heart, plays an important role in neural and cardiac function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly and Al...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720510791050911
更新日期:2010-05-01 00:00:00
abstract::In the present study we set up a model of slow progression of neuronal injury by exposing organotypic hippocampal cultures to a low concentration of Amyloid β (25-35) peptide (Aβ, 2 μM) to analyze the time-related effects of 17-β estradiol (17β-E2, 10 nM). Neuronal death occurs after 7 d and is prevented by addition o...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205013666160125113509
更新日期:2016-01-01 00:00:00
abstract::Based on the amyloid hypothesis, studies for AD therapy have been mostly focused on removing β-amyloid. Recent results of amyloid immunotherapy raised the question whether β-amyloid is sufficient target for AD therapy. Neurofibrillary tangles (NFTs), which contain hyperphosphorylated tau, are another pathological hall...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720510793611600
更新日期:2010-12-01 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Aβ leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reduci...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205015666180404160625
更新日期:2018-01-01 00:00:00
abstract::High levels of cholesterol have been proposed as a risk factor for Alzheimer's disease (AD). Polymorphism of genes encoding proteins that regulate cholesterol metabolism have also been associated with the frequency of Alzheimer's development. Some studies have shown that cholesterol-lowering drugs reduce the frequency...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720510791050821
更新日期:2010-05-01 00:00:00
abstract:BACKGROUND:It is well known that alterations in astrocytes occur in Alzheimer's disease and reactive astrogliosis is one of the hallmarks of the disease. Recently, data has emerged that suggests that alterations in astrocytes may also occur early in the pathogenesis of the disease. OBJECTIVE:The aim of present work wa...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205015666180613113924
更新日期:2018-01-01 00:00:00
abstract::The field of aging and dementia research is advancing rapidly toward the stage of earlier identification of clinical symptoms. Ultimately, clinicians would like to be able to identify individuals who are asymptomatic but at risk for developing dementia. In the interim, the construct of mild cognitive impairment (MCI) ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720509788929237
更新日期:2009-08-01 00:00:00
abstract::Alzheimer's disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently test...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205013666160314145347
更新日期:2017-01-01 00:00:00
abstract:OBJECTIVES:Memory evaluation is a key component in the accurate diagnosis of cognitive disorders.One memory procedure that has shown promise in discriminating disease-related cognitive decline from normal cognitive aging is the New York University Paragraph Recall Test; however, the effects of education have been unexa...
journal_title:Current Alzheimer research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.2174/15672050113109990140
更新日期:2013-09-01 00:00:00
abstract::Alzheimer's disease (AD) is a devastating chronic neurodegenerative disease with currently no available disease modifying treatment. In recent years, the peptide amyloid-beta has been proposed as the major pathogenic force in the development and progression of AD. Microglia, the resident immune and phagocytic cells of...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720509790147179
更新日期:2009-12-01 00:00:00
abstract:BACKGROUND:Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer's disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify n...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205016666181212155147
更新日期:2019-01-01 00:00:00
abstract::A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, suc...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720511795745276
更新日期:2011-06-01 00:00:00