Abstract:
:The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer's disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as β-amyloid (Aβ) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant Aβ deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated Aβ plaques in the cerebral cortex of AD brains, but does not visualize Aβ plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar Aβ brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme's active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.
journal_name
Curr Alzheimer Resjournal_title
Current Alzheimer researchauthors
Darvesh Sdoi
10.2174/1567205013666160404120542subject
Has Abstractpub_date
2016-01-01 00:00:00pages
1173-7issue
10eissn
1567-2050issn
1875-5828pii
CAR-EPUB-74774journal_volume
13pub_type
杂志文章,评审abstract::The occurrence of a plaque-dependent inflammation in Alzheimer's disease has been extensively documented in both human specimens and transgenic models of the disease. Since insoluble plaques are present in AD patients from early preclinical stages of the pathology, the point at which neuroinflammation first occurs in ...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/156720511795255982
更新日期:2011-03-01 00:00:00
abstract:BACKGROUND:Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-infl...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720507783018217
更新日期:2007-12-01 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::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
abstract:BACKGROUND:The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called "amyloid cascade hypothesis" has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflamm...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205014666170505094549
更新日期:2018-02-22 00:00:00
abstract:BACKGROUND:Impairment in instrumental activities of daily living (IADL) emerges in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. Some IADL scales are sensitive to early deficits in MCI, but none have been validated for detecting subtle functional changes in clinically normal ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,多中心研究
doi:10.2174/156720501205150526115003
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND:Previous work designed a network-based protocol of cognitive training. This programme exploits a mechanism of induced task-oriented co-activation of multiple regions that are part of the default mode network (DMN), to induce functional rewiring and increased functional connectivity within this network. OBJE...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205015666171212103323
更新日期:2018-01-01 00:00:00
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::In the last decade, several radiolabeled compounds have been developed for the imaging in vivo of amyloid pathology by means of Positron Emission Tomography (PET). Among these, 18F Florbetaben appear to be one of the most reliable for its high affinity for amyloid plaques in brain and its radio-chemical properties tha...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205013666160620114309
更新日期:2017-01-01 00:00:00
abstract::Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD).The main endogenousantioxidant,glutathione (GSH),has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:
更新日期:2015-03-24 00:00:00
abstract::In this work, we present a fully automatic computer-aided diagnosis method for the early diagnosis of the Alzheimer's disease. We study the distance between classes (labelled as normal controls and possible Alzheimer's disease) calculated in 116 regions of the brain using the Welchs's t-test. We select the regions wit...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205013666160415154852
更新日期:2016-01-01 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::Recent studies have shown that the translocase of outer mitochondrial membrane 40 homolog (TOMM40) contains a polymorphic poly-T variant, the long variant of which is associated with an increase in AD incidence among APOE 3 carriers. Current methods to isotype the poly-T region rely on long PCR, subcloning and sequenc...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/156720512804142921
更新日期:2012-12-01 00:00:00
abstract:OBJECTIVE:Centrifuges are the principal means of generating physiological hypergravity and have been used for many medical purposes, including the therapy of psychiatric diseases and evaluation of vestibular system in the pilots. In particular, modern centrifuges have evolved into mechanically sophisticated precision i...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205015666171229225501
更新日期:2018-01-01 00:00:00
abstract::The currently available experimental data supports the hypothesis that the neuroprotective effect of dimebon is related to the protection of the brain-mitochondria from neurodegeneration. In this study, the influence of dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effe...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205011666140505094808
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:There is a growing body of pre-clinical evidence suggesting that lithium (Li) may protect neurons from a range of neurotoxic insults, hence the term neuroprotective effects. Does Li have similar effects also in human subjects? METHODS:We reviewed the neuroimaging literature investigating the association bet...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205013666160219112712
更新日期:2016-01-01 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::Mutations in presenilin 1 (PS1) cause early-onset familial Alzheimer;s disease (FAD). Although FAD accounts for less than 5% of all cases of Alzheimer;s disease (AD), extensive analyses of PS1 function have elucidated an important neuronal mechanism underling AD pathogenesis. PS1 is considered to be an essential compo...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205043480528
更新日期:2004-02-01 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:BACKGROUND:Life expectancy is increasing all over the world, although neurodegenerative disorders might drastically affect the individual activity of aged people. Of those, Alzheimer's Disease (AD) is one of the most social-cost age-linked diseases of industrialized countries. To date, retinal diseases seem to be more ...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205016666191023114015
更新日期:2019-01-01 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::Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic di...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/1567205012666150710115022
更新日期:2015-01-01 00:00:00
abstract::CATIE-AD was a multicenter effectiveness trial of atypical antipsychotics in patients with agitation and psychosis associated with AD who resided in the community. The study enrolled 421 participants. In this paper we present and discuss baseline characteristics of participants (demographics, cognitive, behavioral, an...
journal_title:Current Alzheimer research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.2174/156720507781077214
更新日期:2007-07-01 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::Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to it...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720506776383068
更新日期:2006-04-01 00:00:00
abstract::Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer's disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids t...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/1567205015666180911151716
更新日期:2018-01-01 00:00:00
abstract::With a longer life expectancy and an increased prevalence of neurodegenerative diseases, investigations on trajectories of cognitive aging have become exciting and promising. This study aimed to estimate the patterns of age-related cognitive decline and the potential associated factors of cognitive function in communi...
journal_title:Current Alzheimer research
pub_type: 杂志文章
doi:10.2174/156720501108140910123112
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians. OBJECTIVES:To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnos...
journal_title:Current Alzheimer research
pub_type: 杂志文章,多中心研究
doi:10.2174/1567205016666190103152425
更新日期:2019-01-01 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::Human memory can be split into familiarity and recollection processes which contribute to different aspects of memory function. These separate processes result in different experiential states. In this review, we examine how this dominant theoretical framework can explain the subjective experience of people with Alzhe...
journal_title:Current Alzheimer research
pub_type: 杂志文章,评审
doi:10.2174/156720509788486545
更新日期:2009-06-01 00:00:00