共查询到20条相似文献,搜索用时 31 毫秒
1.
Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with accumulation of amyloid beta-peptide, synaptic degeneration and the death of neurons in the hippocampus, and temporal, parietal and frontal lobes of the cerebral cortex. Analysis of postmortem brain tissue from AD patients can provide information on molecular alterations present at the end of the disease process, but cannot discriminate between changes that are specifically involved in AD versus those that are simply a consequence of neuronal degeneration. Animal models of AD provide the opportunity to elucidate the molecular changes that occur in brain cells as the disease process is initiated and progresses. To this end, we used the 3xTgAD mouse model of AD to gain insight into the complex alterations in proteins that occur in the hippocampus and cortex in AD. The 3xTgAD mice express mutant presenilin-1, amyloid precursor protein and tau, and exhibit AD-like amyloid and tau pathology in the hippocampus and cortex, and associated cognitive impairment. Using the iTRAQ stable-isotope-based quantitative proteomic technique, we performed an in-depth proteomic analysis of hippocampal and cortical tissue from 16 month old 3xTgAD and non-transgenic control mice. We found that the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth and microtubule dynamics. Our findings have elucidated some of the complex proteome changes that occur in a mouse model of AD, which could potentially illuminate novel therapeutic avenues for the treatment of AD and other neurodegenerative disorders. 相似文献
2.
Minho Moon Eun Sun Jung Seong Gak Jeon Moon‐Yong Cha Yongwoo Jang Woori Kim Claudia Lopes Inhee Mook‐Jung Kwang‐Soo Kim 《Aging cell》2019,18(1)
The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target. 相似文献
3.
Wolz R Julkunen V Koikkalainen J Niskanen E Zhang DP Rueckert D Soininen H Lötjönen J;Alzheimer's Disease Neuroimaging Initiative 《PloS one》2011,6(10):e25446
The role of structural brain magnetic resonance imaging (MRI) is becoming more and more emphasized in the early diagnostics of Alzheimer's disease (AD). This study aimed to assess the improvement in classification accuracy that can be achieved by combining features from different structural MRI analysis techniques. Automatically estimated MR features used are hippocampal volume, tensor-based morphometry, cortical thickness and a novel technique based on manifold learning. Baseline MRIs acquired from all 834 subjects (231 healthy controls (HC), 238 stable mild cognitive impairment (S-MCI), 167 MCI to AD progressors (P-MCI), 198 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were used for evaluation. We compared the classification accuracy achieved with linear discriminant analysis (LDA) and support vector machines (SVM). The best results achieved with individual features are 90% sensitivity and 84% specificity (HC/AD classification), 64%/66% (S-MCI/P-MCI) and 82%/76% (HC/P-MCI) with the LDA classifier. The combination of all features improved these results to 93% sensitivity and 85% specificity (HC/AD), 67%/69% (S-MCI/P-MCI) and 86%/82% (HC/P-MCI). Compared with previously published results in the ADNI database using individual MR-based features, the presented results show that a comprehensive analysis of MRI images combining multiple features improves classification accuracy and predictive power in detecting early AD. The most stable and reliable classification was achieved when combining all available features. 相似文献
4.
Mild cognitive impairment (MCI) is regarded as a transition stage between the cognitive changes of normal aging and the more
serious problems caused by Alzheimer’s disease (AD). Previous studies had demonstrated increased expression of cell cycle
proteins in AD brain. In the present study, we have analyzed the expression of the cell cycle proteins, CDK2, CDK5 and cyclin
G1 in hippocampus and inferior parietal lobule (IPL) in subjects with amnestic mild cognitive impairment and control using
Western blot analysis. The expression of CDK2, CDK5 and cyclin G1 were found to be significantly increased in MCI hippocampus
as well as in IPL compared to control brain. These results suggest that some cells may have re-entered the cell cycle. However,
the expression of CDK2 and CDK5 is greater in MCI hippocampus compared to those of MCI IPL, and hippocampus is a region that
is severely affected by AD pathology. Since these proteins are involved directly or indirectly in microtubule destabilization
and hyperphosphorylation of tau, and also in APP processing we hypothesize that cell cycle disturbance may be important contributor
in the pathogenesis of AD.
Special issue dedicated to Dr. John P. Blass. 相似文献
5.
T W Mitchell J Nissanov L Y Han E J Mufson J A Schneider E J Cochran D A Bennett V M Lee J Q Trojanowski S E Arnold 《The journal of histochemistry and cytochemistry》2000,48(12):1627-1638
Pathological alterations in dendrites and axons (i.e., neuritic pathologies) occur in the normal aging brain as well as in brains from elders with mild cognitive impairment and neurodegenerative dementia. These alterations may correlate with clinical measures of cognitive abilities, but the contribution of neuropil threads (NTs), which constitute 85-90% of cortical tau pathology, has not been clear because of the lack of quantitative methodologies. We combined quantitative fractionation and image analysis to devise a strategy for measuring the burden of tau-rich NTs in the entorhinal and perirhinal cortex of brains from elders with and without cognitive impairment, including dementia due to Alzheimer's disease (AD). On the basis of data presented here using this novel strategy, we conclude that this quantitative imaging technique will facilitate efforts to determine the behavioral correlations of neuritic lesions in AD and other brain disorders. 相似文献
6.
Atrophy of the cortical thickness and gray matter volume are regarded as sensitive markers for the early clinical diagnosis of Alzheimer’s disease (AD). This study aimed to investigate differences in atrophy patterns in the frontal-subcortical circuits between MCI and AD, assess whether these differences were essential for the pathologic basis of cognitive impairment. A total of 131 individuals were recruited, including 45 with cognitively normal controls (CN), 46 with MCI, and 40 with AD. FreeSurfer software was used to perform volumetric measurements of the frontal-subcortical circuits from 3.0T magnetic resonance (MR) scans. Data revealed that both MCI and AD subjects had a thinner cortex in the left caudal middle frontal gyrus and the left lateral orbitofrontal gyrus compared with CN individuals. The left lateral orbitofrontal gyrus was also thinner in AD compared with MCI patients. There were no statistically significant differences in the cortical mean curvature among the three groups. Both MCI and AD subjects exhibited smaller bilateral hippocampus volumes compared with CN individuals. The volumes of the bilateral hippocampus and the right putamen were also smaller in AD compared with MCI patients. Logistic regression analyses revealed that the left lateral orbitofrontal gyrus and bilateral hippocampus were risk factors for cognitive impairment. These current results suggest that atrophy was heterogeneous in subregions of the frontal-subcortical circuits in MCI and AD patients. Among these subregions, the reduced thickness of the left lateral orbitofrontal and the smaller volume of the bilateral hippocampus seemed to be markers for predicting cognitive impairment. 相似文献
7.
Hyunjun Park Yeong-Bae Lee Keun-A Chang 《International journal of biological sciences》2022,18(5):2220
Background and Purpose: Recently, several abnormally regulated microRNAs (miRNAs) have been identified in patients with Alzheimer''s disease (AD). The purpose of this study was to identify abnormally expressed miRNAs and to investigate whether they affect pathological changes in AD in the 5xFAD AD mouse model.Experimental Approach: Using microarray analysis and RT-qPCR, miRNA expression in the hippocampus of a 4-month-old 5xFAD mouse model of AD was investigated. A dual-luciferase assay was performed to determine whether the altered miR-200c regulates the translation of the target mRNA, Ywhag. Whether miR-200c modulates AD pathology was determined in primary hippocampal neurons and C57BL/6J mice transfected with miR-200c inhibitor. In addition, total miRNAs were extracted from the serums of 28 healthy age-matched controls and 22 individual participants with cognitive impairment, and RT-qPCR was performed.Key results: miR-200c expression was reduced in the hippocampus of 5xFAD mice. In primary hippocampal neurons, miR-200c regulated the translation of 14-3-3γ and increased tau phosphorylation (p-tau) by increasing p-GSK-3β (GSK-3β phosphorylation). It was also confirmed that miR-200c inhibition in the hippocampus of C57BL/6J mice induces cognitive impairment and increases tau phosphorylation through 14-3-3γ activation. Finally, aberrant expression of miR-200c was confirmed in the blood serum of human AD patients.Conclusion and Implications: Our results strongly suggest that dysregulation of miR-200c expression contributes to the pathogenesis of AD, including cognitive impairment through hyperphosphorylated tau. 相似文献
8.
Alzheimer’s disease (AD) is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI) and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects. 相似文献
9.
Lee JH Agacinski G Williams JH Wilcock GK Esiri MM Francis PT Wong PT Chen CP Lai MK 《Neurochemistry international》2010,57(8):985-989
The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer's disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD. 相似文献
10.
Rui Liu Meiruo Xiang Luke C. Pilling David Melzer Lihong Wang Kevin J. Manning David C. Steffens Jack Bowden Richard H. Fortinsky George A. Kuchel Taeho G. Rhee Breno S. Diniz Chia-Ling Kuo 《Aging cell》2023,22(7):e13808
Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90–0.96, p = 3.37 × 10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies. 相似文献
11.
Proteomic identification of nitrated brain proteins in amnestic mild cognitive impairment: a regional study 总被引:2,自引:0,他引:2
Sultana R Reed T Perluigi M Coccia R Pierce WM Butterfield DA 《Journal of cellular and molecular medicine》2007,11(4):839-851
Oxidative stress is an imbalance between the level of antioxidants and oxidants in a cell. Oxidative stress has been shown in brain of subjects with mild cognitive impairment (MCI) as well Alzheimer's disease (AD). MCI is considered as a transition phase between control and AD. The focus of the current study was to identify nitrated proteins in the hippocampus and inferior parietal lobule (IPL) brain regions of subjects with amnestic MCI using proteomics. The identified nitrated proteins in MCI brain were compared to those previously reported to be nitrated and oxidatively modified in AD brain, a comparison that might provide an invaluable insight into the progression of the disease. 相似文献
12.
Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model 总被引:11,自引:0,他引:11
Yoshiyama Y Higuchi M Zhang B Huang SM Iwata N Saido TC Maeda J Suhara T Trojanowski JQ Lee VM 《Neuron》2007,53(3):337-351
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders. 相似文献
13.
Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice 总被引:23,自引:0,他引:23
Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction. 相似文献
14.
Fukushima T Nakamura A Iwakami N Nakada Y Hattori H Hoki S Yamaguchi H Nakagawa M Terashima N Narita H 《Biochemical and biophysical research communications》2011,407(4):730-734
Tau pathology is implicated in mechanisms of neurodegenerative tauopathies, including Alzheimer’s disease (AD) and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). It has been reported that transgenic mice expressing FTDP-17 mutation P301L of human tau (P301L mice) display extensive tau pathology and exhibit behavioral deficits with aging. In this study, we investigated the effects of T-817MA, a neuroprotective agent, on the motor and cognitive impairments associated with neuronal degeneration in P301L mice. T-817MA prevented the progression of motor deficit and the loss of spinal cord motor neurons in P301L mice. Furthermore, T-817MA significantly attenuated the spatial memory impairment and the reduction in synaptic terminal density in the hippocampal dentate gyrus of P301L mice. These results indicate that T-817MA improved the motor and cognitive impairments as a result of inhibiting neuronal degeneration derived from tau pathology in the P301L mice. Therefore, it is expected that T-817MA has a therapeutic potential for tau-related neurodegenerative diseases such as AD. 相似文献
15.
Recent reports demonstrate that the activation and interaction of the protease calpain (CP) and the protein phosphatase calcineurin (CN) are elevated in the late stages of Alzheimer’s disease (AD). However, the extent to which CPs and CN interact during earlier stages of disease progression remains unknown. Here, we investigated CP and CN protein levels in cytosolic, nuclear, and membrane fractions prepared from human postmortem hippocampal tissue from aged non‐demented subjects, and subjects diagnosed with mild cognitive impairment (MCI). The results revealed a parallel increase in CP I and the 48 kDa CN‐Aα (ΔCN‐Aα48) proteolytic fragment in cytosolic fractions during MCI. In primary rat hippocampal cultures, CP‐dependent proteolysis and activation of CN was stimulated by application of oligomeric Aβ(1–42) peptides. Deleterious effects of Aβ on neuronal morphology were reduced by blockade of either CP or CN. NMDA‐type glutamate receptors, which help regulate cognition and neuronal viability, and are modulated by CPs and CN, were also investigated in human hippocampus. Relative to controls, MCI subjects showed significantly greater proteolytic levels of the NR2B subunit. Within subjects, the extent of NR2B proteolysis was strongly correlated with the generation of ΔCN‐Aα48 in the cytosol. A similar proteolytic pattern for NR2B was also observed in primary rat hippocampal cultures treated with oligomeric Aβ and prevented by inhibition of CP or CN. Together, the results demonstrate that the activation and interaction of CPs and CN are increased early in cognitive decline associated with AD and may help drive other pathologic processes during disease progression. 相似文献
16.
Rulon LL Robertson JD Lovell MA Deibel MA Ehmann WD Markesber WR 《Biological trace element research》2000,75(1-3):79-85
Concentrations of zinc in postmortem serum and four brain regions were measured by flame atomic absorption spectrometry and
instrumental neutron activation analysis, respectively, in nine Alzheimer’s disease (AD) and eight control subjects. A statistically
significant elevation of zinc serum was observed in AD subjects (136.4±66.8 μg/dL) compared with age-matched control subjects
(71.1±35.0 μg/dL). No significant differences were observed between AD and control zinc concentrations in the amygdala, hippocampus,
cerebellum, and superior and middle temporal gryi. 相似文献
17.
Desikan RS Sabuncu MR Schmansky NJ Reuter M Cabral HJ Hess CP Weiner MW Biffi A Anderson CD Rosand J Salat DH Kemper TL Dale AM Sperling RA Fischl B;Alzheimer's Disease Neuroimaging Initiative 《PloS one》2010,5(9):e12853
Background
Alzheimer''s disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.Methodology/Principal Findings
In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer''s pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.Conclusions/Significance
Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer''s pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia. 相似文献18.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2016,1860(6):1291-1298
BackgroundThe prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions.MethodsIntrahippocampal administration of a novel anti-Aβ domain antibody for aggregated Aβ, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured.ResultsDIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration.ConclusionsOur findings support the concept that oligomeric Aβ within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia.General Significance and InterestOur work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state. 相似文献
19.
Klein WL 《Neurochemistry international》2002,41(5):345-352
Over the past several years, experiments with synthetic amyloid-beta peptide (Abeta) and animal models have strongly suggested that pathogenesis of Alzheimer's disease (AD) involves soluble assemblies of Abeta peptides (Trends Neurosci. 24 (2001) 219). These soluble neurotoxins (known as ADDLs and protofibrils) seem likely to account for the imperfect correlation between insoluble fibrillar amyloid deposits and AD progression. Recent experiments have detected the presence of ADDLs in AD-afflicted brain tissue and in transgenic-mice models of AD. The presence of high affinity ADDL binding proteins in hippocampus and frontal cortex but not cerebellum parallels the regional specificity of AD pathology and suggests involvement of a toxin receptor-mediated mechanism. The properties of ADDLs and their presence in AD-afflicted brain are consistent with their putative role even in the earliest stages of AD, including forms of mild cognitive impairment. 相似文献
20.
Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD. 相似文献