Abstract：
:Extracellular senile plaques (SPs) are hallmark brain lesions of sporadic Alzheimer's disease (AD) and the likely consequence of genetic mutations that cause familial AD by increasing production of amyloidogenic amyloid-beta (Abeta). Although Abeta vaccines and inhibitors of amyloidogenic secretases are potential AD therapies, multifaceted strategies may be needed to effectively interrupt Abeta amyloidosis and prevent/arrest AD. One such strategy is the inhibition of Abeta fibrillization as a potential therapy for AD. Certain amyloid-binding molecules, such as Congo red (CR) and chrysamine G (CG) and Thioflavin S (TS) have been shown to bind SPs with high affinity and they can also arrest the formation of Abeta fibrils; however, CR, CG and TS are unsuitable for AD therapy because they do not cross the blood brain barrier (BBB). Therefore, we have generated novel CG and TS derivatives that specifically recognize fibrillar Abeta in vitro, arrest the formation of Abeta fibrils, and cross the BBB of transgenic (TG) mice that model AD amyloidosis. As proof of their ability to cross the BBB and of their high specificity for Abeta fibrils in vivo, we show that following intravenous injection in TG mice these compounds specifically label AD-like brain deposits of fibrillar Abeta. Furthermore, we demonstrate that CG derivative IMSB binds to SPs comprised of Abeta40 with much higher affinity than Abeta42 whereas TS derivative TDZM shows the opposite affinity. Moreover, IMSB but not TDZM binds selectively to neurofibrillary tangles. Significantly both IMSB and TDZM inhibit Abeta fibrillization in test tubes and in cultured cells. Thus, small amyloid binding molecules such as IMSB and TDZM which cross the BBB are potential therapeutic agents for the treatment of AD.
journal_name
Neurobiol Agingjournal_title
Neurobiology of agingauthors
Lee VMdoi
10.1016/s0197-4580(02)00121-5subject
Has Abstractpub_date
2002-11-01 00:00:00pages
1039-42issue
6eissn
0197-4580issn
1558-1497pii
S0197458002001215journal_volume
23pub_type
杂志文章,评审abstract：:Individuals with Down syndrome (DS), caused by trisomy of chromosome 21, inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques, neurofibrillary tangles, and neuronal loss. Amyloid-β protein, the major component of neuritic plaques, is the proteolytic product of amyloid-β...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.07.029
更新日期：2015-01-01 00:00:00
abstract：:The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransm...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(89)80008-9
更新日期：1989-01-01 00:00:00
abstract：:Mimicking relevant behavioral features of the human pathology is one of the most important challenges for animal models of neurological disorders including Alzheimer disease (AD). Indeed, the most popular genetic AD mouse lines bearing mutations of the amyloid precursor protein (APP) and presenilin 1 genes (PS1), ofte...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2011.09.012
更新日期：2012-05-01 00:00:00
abstract：:Despite cognitive and physical declines, it has been suggested that older adults remain able to regulate their emotions effectively. However, whether this is true for all emotion regulation processes has not been established. We hypothesized that cognitive reappraisal, a form of emotion regulation requiring intact cog...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2010.06.004
更新日期：2012-04-01 00:00:00
abstract：:Aged rats show decrements in performance on cognitive tasks that require the use of spatial learning and memory. We used the 8-arm radial water maze (RAWM) to measure spatial learning as a function of age in young (6 months) and old (21 months) male F344 rats. Rats were placed in the RAWM in different start arms with ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(03)00041-1
更新日期：2004-02-01 00:00:00
abstract：:Since the introduction of amyloid imaging nearly 10 years ago, this technique has gained widespread use and acceptance. More recently, published reports have begun to appear in which amyloid imaging is used to detect the effects of antiamyloid therapies. This review will consider the issues involved in the use of amyl...
journal_title：Neurobiology of aging
pub_type： 杂志文章,评审
doi：10.1016/j.neurobiolaging.2011.09.006
更新日期：2011-12-01 00:00:00
abstract：:Spreading depolarizations (SDs) occur spontaneously in the brain after stroke, exacerbate ischemic injury, and thus emerge as a potential target of intervention. Aging predicts worse outcome from stroke; yet, the impact of age on SD evolution is not clear. Cerebral ischemia was induced by bilateral common carotid arte...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2015.08.014
更新日期：2015-12-01 00:00:00
abstract：:Apolipoprotein E (APOE) ε4 is a major risk factor for Alzheimer's disease (AD) and dementia, but not all ε4 carriers develop dementia. We sought to identify factors that may play a role in modifying the risk of dementia due to ε4. A cognitively intact cohort (n = 932, age ≥ 75) was followed for 9 years to detect incid...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2012.03.003
更新日期：2013-01-01 00:00:00
abstract：:An association between semicarbazide-sensitive amine oxidase (SSAO) and cerebral amyloid angiopathy (CAA) related to Alzheimer's disease (AD) has been largely postulated. Increased SSAO activity and expression have been detected in cerebrovascular tissue and plasma of AD patients, colocalizing with cerebrovascular amy...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.09.030
更新日期：2015-02-01 00:00:00
abstract：:Aged, cognitively-impaired rats (and humans) show hypothalamic-pituitary-adrenal (HPA) hyperactivity that correlates with hippocampal damage. The resultant increase in plasma glucocorticoid exposure is thought to contribute to impaired hippocampal function and to potentiate hippocampal neuron death. In young, adult ra...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(97)00103-6
更新日期：1997-09-01 00:00:00
abstract：:In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer's disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to u...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2010.06.015
更新日期：2012-01-01 00:00:00
abstract：:In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin tra...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2010.03.023
更新日期：2012-03-01 00:00:00
abstract：:The observation that neurons containing neurofibrillary tangles are usually adjacent to neurons free of any morphological indication of disease, suggests the hypothesis that it is NFT-bearing neurons that are primarily responsible for the loss of function in AD. Quantitative Golgi postmortem studies from our laborator...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(95)00035-d
更新日期：1995-05-01 00:00:00
abstract：:The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2004.09.001
更新日期：2005-01-01 00:00:00
abstract：:Activated microglia are instrumental to neurodegeneration in Parkinson's disease (PD). Fractalkine, as an exclusive ligand for CX3CR1 expressed on microglia, has recently been reported to be released out by neurons, and induce microglial activation as a neuron-to-glia signal in the spinal cord. However, the role of fr...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2009.03.004
更新日期：2011-03-01 00:00:00
abstract：:The classic hallmarks of Alzheimer's disease are the deposition of amyloid in plaques and in the cerebrovasculature, and the emergence of neurofibrillary tangles in neurons. The interplay between these two pathologic processes, on the one hand, and the degeneration of neurons and loss of cognitive functions on the oth...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(95)02074-8
更新日期：1996-03-01 00:00:00
abstract：:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by an extensive loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Genetic studies report a high heritability of ALS. Recently, whole-exome sequencing analysis of familial ALS (FALS) patients allow...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2015.09.013
更新日期：2016-01-01 00:00:00
abstract：:Neurokinin B and its cognate neurokinin-3 receptor are expressed more in the forebrain than in brain stem structures but little is known about the primary function of this peptide system in the central processing of information. In general, few studies have specifically addressed age-related changes of tachykinins, no...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(99)00019-6
更新日期：1999-01-01 00:00:00
abstract：:Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome seq...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2017.06.007
更新日期：2017-10-01 00:00:00
abstract：:An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2005.07.021
更新日期：2006-03-01 00:00:00
abstract：:The effect of aging on acquisition of a learned suppression of photopositive tendencies was studied in 1-7-week-old flies of both sexes. Flies had to choose in a T-maze between an alley leading to a lighted vial associated with an aversive stimulus, a quinine hydrochloride solution, and another alley leading to a dark...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2003.12.004
更新日期：2004-10-01 00:00:00
abstract：:Cerebral gray-matter volume (GMV) decreases in normal aging but the extent of the decrease may be experience-dependent. Bilingualism may be one protective factor and in this article we examine its potential protective effect on GMV in a region that shows strong age-related decreases-the left anterior temporal pole. Th...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.03.010
更新日期：2014-09-01 00:00:00
abstract：:Mutants of presenilin 1 (PS1) increase neuronal cell death causing autosomal-dominant familial Alzheimer's disease (FAD). Recent literature shows that treatment of neuronal cultures with low concentrations of trypsin, a member of the serine family of proteases, protects neurons from toxic insults by binding to the pro...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2016.02.028
更新日期：2016-06-01 00:00:00
abstract：:Vergence eye movements were recorded with the scleral search-coil system in 32 healthy subjects (ages 19-73 years) to characterize the age-related effects on the dynamic parameters of vergence responses to step (transient components) and ramp or sinusoidal targets (sustained components) under natural viewing condition...
journal_title：Neurobiology of aging
pub_type： 临床试验,杂志文章
doi：10.1016/j.neurobiolaging.2005.01.002
更新日期：2006-01-01 00:00:00
abstract：:The current study describes both Abeta and tau abnormalities that accumulate in the brains of aged (16-21 years), but not young (<4 years) clinically characterized cats. Diffuse plaques that were morphologically different from what is typically observed in the human brain could be detected with 4G8 (Abeta17-24) or an ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2004.06.015
更新日期：2005-05-01 00:00:00
abstract：:Vascular disease and Alzheimer's disease are both common disorders, in particular among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemi...
journal_title：Neurobiology of aging
pub_type： 杂志文章,评审
doi：10.1016/s0197-4580(99)00110-4
更新日期：2000-03-01 00:00:00
abstract：:Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease caused by an abnormal expansion of a tandem CAG repeat in exon 1 of the androgen receptor (AR) gene that results in an abnormally long polyglutamine tract (polyQ) in the AR protein. As a result, the mutant AR (ARpolyQ) misfolds, forming cytopl...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2013.05.026
更新日期：2013-11-01 00:00:00
abstract：:Linkage data in Alzheimer's disease have not firmly established a genetic locus on chromosome 21 in early onset disease families. There is little or no support for a chromosome 21 locus in late onset families. Differences in the selection of families and the analysis of data accounts for the differences in interpretat...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(89)90083-3
更新日期：1989-09-01 00:00:00
abstract：:This paper reports a series of experiments that assessed learning and memory performance in aged rats from a neuropsychological perspective. Relative to young adults, old rats displayed rapid rates of forgetting, increased susceptibility to interference, and poor long-term recall of specific experiences. There were no...
journal_title：Neurobiology of aging
pub_type： 杂志文章,评审
doi：10.1016/s0197-4580(88)80102-7
更新日期：1988-09-01 00:00:00
abstract：:Calmodulin (CaM) and tubulin were analyzed by radioimmunoassay in subcellular fractions prepared from cerebral cortex and striatum of aging male C57BL/6J mice. Three fractions were prepared by a new procedure: cytosol (soluble); EGTA-releasable, membrane-bound; and detergent-extractable (Triton X-100), membrane-bound ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(87)90022-4
更新日期：1987-03-01 00:00:00
