共查询到20条相似文献，搜索用时 31 毫秒
1.
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP 总被引：2，自引：0，他引：2
Lewis J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E 《Science (New York, N.Y.)》2001,293(5534):1487-1491
JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease. 相似文献
2.
Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils 总被引：1，自引：0，他引：1
beta-Amyloid plaques and neurofibrillary tangles (NFTs) are the defining neuropathological hallmarks of Alzheimer's disease, but their pathophysiological relation is unclear. Injection of beta-amyloid Abeta42 fibrils into the brains of P301L mutant tau transgenic mice caused fivefold increases in the numbers of NFTs in cell bodies within the amygdala from where neurons project to the injection sites. Gallyas silver impregnation identified NFTs that contained tau phosphorylated at serine 212/threonine 214 and serine 422. NFTs were composed of twisted filaments and occurred in 6-month-old mice as early as 18 days after Abeta42 injections. Our data support the hypothesis that Abeta42 fibrils can accelerate NFT formation in vivo. 相似文献
3.
Meyer-Luehmann M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M 《Science (New York, N.Y.)》2006,313(5794):1781-1784
Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-beta (Abeta)-containing brain extracts from humans with Alzheimer's disease or beta-amyloid precursor protein (APP) transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Abeta immunodepletion, protein denaturation, or by Abeta immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains. 相似文献
4.
Tan J Town T Paris D Mori T Suo Z Crawford F Mattson MP Flavell RA Mullan M 《Science (New York, N.Y.)》1999,286(5448):2352-2355
Alzheimer's disease (AD) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. CD40 expression was increased on cultured microglia treated with freshly solublized amyloid-beta (Abeta, 500 nanomolar) and on microglia from a transgenic murine model of AD (Tg APPsw). Increased tumor necrosis factor alpha production and induction of neuronal injury occurred when Abeta-stimulated microglia were treated with CD40 ligand (CD40L). Microglia from Tg APPsw mice deficient for CD40L demonstrated reduction in activation, suggesting that the CD40-CD40L interaction is necessary for Abeta-induced microglial activation. Finally, abnormal tau phosphorylation was reduced in Tg APPsw animals deficient for CD40L, suggesting that the CD40-CD40L interaction is an early event in AD pathogenesis. 相似文献
5.
Zhou Y Su Y Li B Liu F Ryder JW Wu X Gonzalez-DeWhitt PA Gelfanova V Hale JE May PC Paul SM Ni B 《Science (New York, N.Y.)》2003,302(5648):1215-1217
A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity. 相似文献
6.
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics 总被引：3，自引：0，他引：3
It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance. 相似文献
7.
Lustbader JW Cirilli M Lin C Xu HW Takuma K Wang N Caspersen C Chen X Pollak S Chaney M Trinchese F Liu S Gunn-Moore F Lue LF Walker DG Kuppusamy P Zewier ZL Arancio O Stern D Yan SS Wu H 《Science (New York, N.Y.)》2004,304(5669):448-452
Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD. 相似文献
8.
Deposits of amyloid beta protein in the central nervous system of transgenic mice. 总被引：10，自引：0，他引：10
D O Wirak R Bayney T V Ramabhadran R P Fracasso J T Hart P E Hauer P Hsiau S K Pekar G A Scangos B D Trapp 《Science (New York, N.Y.)》1991,253(5017):323-325
Alzheimer's disease is characterized by widespread deposition of amyloid in the central nervous system. The 4-kilodalton amyloid beta protein is derived from a larger amyloid precursor protein and forms amyloid deposits in the brain by an unknown pathological mechanism. Except for aged nonhuman primates, there is no animal model for Alzheimer's disease. Transgenic mice expressing amyloid beta protein in the brain could provide such a model. To investigate this possibility, the 4-kilodalton human amyloid beta protein was expressed under the control of the promoter of the human amyloid precursor protein in two lines of transgenic mice. Amyloid beta protein accumulated in the dendrites of some but not all hippocampal neurons in 1-year-old transgenic mice. Aggregates of the amyloid beta protein formed amyloid-like fibrils that are similar in appearance to those in the brains of patients with Alzheimer's disease. 相似文献
9.
DeMattos RB Bales KR Cummins DJ Paul SM Holtzman DM 《Science (New York, N.Y.)》2002,295(5563):2264-2267
The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD. 相似文献
10.
Iwata N Tsubuki S Takaki Y Shirotani K Lu B Gerard NP Gerard C Hama E Lee HJ Saido TC 《Science (New York, N.Y.)》2001,292(5521):1550-1552
Amyloid beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate Abeta-degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered Abeta and in the metabolic suppression of the endogenous Abeta levels in a gene dose-dependent manner. The regional levels of Abeta in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest level and cerebellum the lowest, correlating with the vulnerability to Abeta deposition in brains of humans with AD. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation. 相似文献
11.
12.
Protein aggregation is involved in the pathogenesis of neurodegenerative diseases and hence is considered an attractive target for therapeutic intervention. However, protein-protein interactions are exceedingly difficult to inhibit. Small molecules lack sufficient steric bulk to prevent interactions between large peptide surfaces. To yield potent inhibitors of beta-amyloid (Abeta) aggregation, we synthesized small molecules that increase their steric bulk by binding to chaperones but also have a moiety available for interaction with Abeta. This strategy yields potent inhibitors of Abeta aggregation and could lead to therapeutics for Alzheimer's disease and other forms of neurodegeneration. 相似文献
13.
Ertekin-Taner N Graff-Radford N Younkin LH Eckman C Baker M Adamson J Ronald J Blangero J Hutton M Younkin SG 《Science (New York, N.Y.)》2000,290(5500):2303-2304
Plasma Abeta42 (amyloid beta42 peptide) is invariably elevated in early-onset familial Alzheimer's disease (AD), and it is also increased in the first-degree relatives of patients with typical late-onset AD (LOAD). To detect LOAD loci that increase Abeta42, we used plasma Abeta42 as a surrogate trait and performed linkage analysis on extended AD pedigrees identified through a LOAD patient with extremely high plasma Abeta. Here, we report linkage to chromosome 10 with a maximal lod score of 3.93 at 81 centimorgans close to D10S1225. Remarkably, linkage to the same region was obtained independently in a genome-wide screen of LOAD sibling pairs. These results provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta. 相似文献
14.
One hundred years ago a small group of psychiatrists described the abnormal protein deposits in the brain that define the most common neurodegenerative diseases. Over the past 25 years, it has become clear that the proteins forming the deposits are central to the disease process. Amyloid-beta and tau make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments. Tau inclusions are also found in a number of related disorders. Genetic studies have shown that dysfunction of amyloid-beta or tau is sufficient to cause dementia. The ongoing molecular dissection of the neurodegenerative pathways is expected to lead to a true understanding of disease pathogenesis. 相似文献
15.
The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa. 相似文献
16.
The primary structure and heterogeneity of tau protein from mouse brain 总被引：74，自引：0，他引：74
Tau protein is a family of microtubule binding proteins, heterogeneous in molecular weight, that are induced during neurite outgrowth and are found prominently in neurofibrillary tangles in Alzheimer's disease. The predicted amino acid sequences of two forms of tau protein from mouse brain were determined from complementary DNA clones. These forms are identical in their amino-terminal sequences but differ in their carboxyl-terminal domains. Both proteins contain repeated sequences that may be tubulin binding sites. The sequence suggests that tau is an elongated molecule with no extensive alpha-helical or beta-sheet domains. These complementary DNAs should enable the study of various functional domains of tau and the study of tau expression in normal and pathological states. 相似文献
17.
Brody DL Magnoni S Schwetye KE Spinner ML Esparza TJ Stocchetti N Zipfel GJ Holtzman DM 《Science (New York, N.Y.)》2008,321(5893):1221-1224
The amyloid-beta peptide (Abeta) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Abeta concentrations and neurological status, with Abeta concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Abeta concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Abeta concentration. 相似文献
18.
Chesebro B Trifilo M Race R Meade-White K Teng C LaCasse R Raymond L Favara C Baron G Priola S Caughey B Masliah E Oldstone M 《Science (New York, N.Y.)》2005,308(5727):1435-1439
In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases. 相似文献
19.
Opposing activities protect against age-onset proteotoxicity 总被引：1，自引：0，他引：1
Cohen E Bieschke J Perciavalle RM Kelly JW Dillin A 《Science (New York, N.Y.)》2006,313(5793):1604-1610
20.
Giasson BI Forman MS Higuchi M Golbe LI Graves CL Kotzbauer PT Trojanowski JQ Lee VM 《Science (New York, N.Y.)》2003,300(5619):636-640
Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases. 相似文献