Alzheimer neurofibrillary lesions: Molecular nature and potential roles of different components

Yen, Shu Hui; Liu, Wan Kyng; Hall, Frederick L.; Yan, Shi Du; Stern, David M.; Dickson, Dennis W.

doi:10.1016/0197-4580(95)00022-7

Cited by 48 publications

(19 citation statements)

References 66 publications

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“…26 Senile plaques occur with various morphologies, including compact or dense-core plaques, as well as diffuse aggregates, all resulting from deposition of the amyloid-␤ peptide in the brain. 27,28 It is known that the amyloid-␤ peptides deposit in ␤-pleated sheet conformation in dense-core plaques, allowing easy detection with histological stains that recognize ␤-sheet structures, and not necessarily amyloid-␤ specifically. 29 Antibodies, however, recognize distinct epitopes of the amyloid-␤ peptide, and can be used to target both dense-core and diffuse deposits.…”

Section: Resultsmentioning

confidence: 99%

Fluorescence resonance energy transfer determinations using multiphoton fluorescence lifetime imaging microscopy to characterize amyloid-beta plaques

et al. 2003

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We describe the implementation of a commercial fluorescence lifetime imaging microscopy (FLIM) instrument used in conjunction with a commercial laser scanning multiphoton microscope. The femtosecond-pulsed near-infrared laser is an ideal excitation source for time-domain fluorescence lifetime measurements. With synchronization from the x-y scanners, fluorescence lifetimes can be acquired on a pixel-by-pixel basis, with high spatial resolution. Multiexponential curve fits for each pixel result in two-dimensional fluorescence resonance energy transfer (FRET) measurements that allow the determination of both proximity of fluorescent FRET pairs, as well as the fraction of FRET pairs close enough for FRET to occur. Experiments are described that characterize this system, as well as commonly used reagents valuable for FRET determinations in biological systems. Constructs of CFP and YFP were generated to demonstrate FRET between this pair of green fluorescent protein (GFP) color variants. The lifetime characteristics of the FRET pair fluorescein and rhodamine, commonly used for immunohistochemistry, were also examined. Finally, these fluorophores were used to demonstrate spatially resolved FRET with senile plaques obtained from transgenic mouse brain. Together these results demonstrate that FLIM allows sensitive measurements of protein-protein interactions on a spatial scale less than 10 nm using commercially available components.

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Section: Resultsmentioning

confidence: 99%

Fluorescence resonance energy transfer determinations using multiphoton fluorescence lifetime imaging microscopy to characterize amyloid-beta plaques

et al. 2003

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“…One of the major pathological features of AD and other tauopathies is the accumulation of abnormally phosphorylated forms of tau in the brains of affected individuals (25). Phosphorylation of tau at serines and threonines that are followed by a proline residue (SP/TP sites) is particularly characteristic of neurodegenerative disease tissue (33). Antibodies AT8, AT100, AT180, TG3, and PHF1, which recognize tau phosphorylated at SP/TP sites, specifically reacted with the brains of tau R406W -expressing flies but not with those of control flies ( Figure 5A) (27)(28)(29).…”

Section: Oxidative Stress Mediates Neurotoxicity In a Drosophila Tauomentioning

confidence: 99%

Oxidative stress mediates tau-induced neurodegeneration in Drosophila

Dias‐Santagata¹,

Fulga²,

Duttaroy³

et al. 2007

J. Clin. Invest.

271

225

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Markers of oxidative damage have been detected in brain tissue from patients with Alzheimer disease (AD) and other neurodegenerative disorders. These findings implicate oxidative injury in the neurodegenerative process, but whether oxidative stress is a cause or a consequence of neurotoxicity remains unclear. We used a Drosophila model of human tauopathies to investigate the role of oxidative stress in neurodegeneration. Genetic and pharmacological manipulation of antioxidant defense mechanisms significantly modified neurodegeneration in our model, suggesting that oxidative stress plays a causal role in neurotoxicity. We demonstrate that the JNK signaling pathway is activated in our model, which is in agreement with previous findings in AD tissue. Furthermore, we show that the extent of JNK activation correlates with the degree of tau-induced neurodegeneration. Finally, our findings suggest that oxidative stress acts not to promote tau phosphorylation, but to enhance tau-induced cell cycle activation. In summary, our study identifies oxidative stress as a causal factor in tau-induced neurodegeneration in Drosophila.

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“…As microtubule-associated cytoskeleton proteins, they play a critical role in the formation and stabilization of the neuron's microtubule system. In a number of pathological conditions, the protein becomes hyperphosphorylated, dissociates from the microtubule, and forms aggregates of paired twisted filaments recognized as NFTs [Yen et al, 1995].…”

Section: Tau and Phospho-tau Proteinsmentioning

confidence: 99%

Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

Wan¹,

Hurko²,

Day³

et al. 2009

Drug Development Research

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Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of age-related dementia. Currently available pharmacologic therapies, including acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, only treat symptoms and do not address the underlying neurodegeneration. In addition to potentially improve the accuracy of diagnosis, biomarkers serve important roles for the development of putative disease-modifying drugs for AD. In this article, we review the existing and emerging areas of biomarker research and development for AD. Biochemical biomarkers in cerebrospinal fluid have been used to provide a link to disease pathology and may provide important proof of concept data for several classes of emerging therapeutics. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or radioligands binding to amyloid plaque are discussed. Appropriate uses of these biomarkers in the context of the development of disease-modifying therapies are discussed. Drug Dev Res 70 : 60-69, 2009.

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Alzheimer neurofibrillary lesions: Molecular nature and potential roles of different components

Cited by 48 publications

References 66 publications

Fluorescence resonance energy transfer determinations using multiphoton fluorescence lifetime imaging microscopy to characterize amyloid-beta plaques

Fluorescence resonance energy transfer determinations using multiphoton fluorescence lifetime imaging microscopy to characterize amyloid-beta plaques

Oxidative stress mediates tau-induced neurodegeneration in Drosophila

Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

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