The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
Bradley T Hyman - One of the best experts on this subject based on the ideXlab platform.
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oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near Senile Plaques
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Robert M Koffie, Bradley T Hyman, Melanie Meyerluehmann, Tadafumi Hashimoto, Kenneth W Adams, Matthew L Mielke, Monica Garciaalloza, Kristina D Micheva, Stephen J Smith, Tara L SpiresjonesAbstract:Synapse loss correlates with a cognitive decline in Alzheimer's disease (AD), but whether this is caused by fibrillar deposits known as Senile Plaques or soluble oligomeric forms of amyloid β (Aβ) is controversial. By using array tomography, a technique that combines ultrathin sectioning of tissue with immunofluorescence, allowing precise quantification of small structures, such as synapses, we have tested the hypothesis that oligomeric Aβ surrounding Plaques contributes to synapse loss in a mouse model of AD. We find that Senile Plaques are surrounded by a halo of oligomeric Aβ. Analysis of >14,000 synapses (represented by PSD95-stained excitatory synapses) shows that there is a 60% loss of excitatory synapses in the halo of oligomeric Aβ surrounding Plaques and that the density increases to reach almost control levels in volumes further than 50 μm from a plaque in an approximately linear fashion (linear regression, r2 = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Aβ associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Aβ. The proportion of excitatory synapses associated with Aβ correlates with decreasing density (correlation, −0.588; P < 0.0001). These data show that Senile Plaques are a potential reservoir of oligomeric Aβ, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of “plaque” vs. “oligomeric Aβ” as the synaptotoxic species in the brain of AD patients.
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lrp and Senile Plaques in alzheimer s disease colocalization with apolipoprotein e and with activated astrocytes
Molecular Brain Research, 2002Co-Authors: Katrin Arelin, Ayae Kinoshita, Christa M Whelan, Michael C Irizarry, William G Rebeck, Dudley K Strickland, Bradley T HymanAbstract:Abstract The low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which is present on Senile Plaques in Alzheimer’s disease (AD). It is suggested to play an important role in the balance between amyloid beta (Aβ) synthesis and clearance mechanisms. One of its ligands, apolipoprotein E (apoE), is also present on Senile Plaques and has been implicated as a risk factor for AD, potentially affecting the deposition, fibrillogenesis and clearance of Aβ. Using immunohistochemistry we show that LRP was present only on cored, apoE-containing Senile Plaques, in both PDAPP transgenic mice and human AD brains. We detected strong LRP staining in neurons and in reactive astrocytes, and immunostaining of membrane-bound LRP showed colocalization with fine astrocytic processes surrounding Senile Plaques. LRP was not present in Plaques in young transgenic mice or in Plaques of APOE-knockout mice. As LRP ligands associated with Aβ deposits in AD brain may play an important role in inducing levels of LRP in both neurons and astrocytes, our findings support the idea that apoE might be involved in upregulation of LRP (present in fine astrocytic processes) and act as a local scaffolding protein for LRP and Aβ. The upregulation of LRP would allow increased clearance of LRP ligands as well as clearance of Aβ/ApoE complexes.
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growth arrest of individual Senile Plaques in a model of alzheimer s disease observed by in vivo multiphoton microscopy
The Journal of Neuroscience, 2001Co-Authors: Richard H Christie, Brian J Bacskai, Warren R Zipfel, Rebecca M Williams, Stephen T Kajdasz, Watt W Webb, Bradley T HymanAbstract:In Alzheimer's disease, amyloid-β peptide aggregates in the extracellular space to form Senile Plaques. The process of plaque deposition and growth has been modeled on the basis of in vitro experiments in ways that lead to divergent predictions: either a diffusion-limited growth model in which Plaques grow by first-order kinetics, or a dynamic model of continual deposition and asymmetrical clearance in which Plaques reach a stable size and stop growing but evolve morphologically over time. The models have not been tested in vivo because Plaques are too small (by several orders of magnitude) for conventional imaging modalities. We now report in vivo multiphoton laser scanning imaging of thioflavine S-stained Senile Plaques in the Tg2576 transgenic mouse model of Alzheimer's disease to test these biophysical models and show that there is no detectable change in plaque size over extended periods of time. Qualitatively, geometric features remain unchanged over time in the vast majority of the 349 Plaques imaged and re-imaged. Intervals as long as 5 months were obtained. Nonetheless, rare examples of growth or shrinkage of individual Plaques do occur, and new Plaques appear between imaging sessions. These results indicate that thioflavine S-positive Plaques appear and then are stable, supporting a dynamic feedback model of plaque growth.
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aggregation and disaggregation of Senile Plaques in alzheimer disease
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Luis Cruz, Brigita Urbanc, Sergey V Buldyrev, R Christie, Teresa Gomezisla, Shlomo Havlin, Megan J Mcnamara, H E Stanley, Bradley T HymanAbstract:We quantitatively analyzed, using laser scan- ning confocal microscopy, the three-dimensional structure of individual Senile Plaques in Alzheimer disease. We carried out the quantitative analysis using statistical methods to gain insights about the processes that govern Ab peptide deposi- tion. Our results show that Plaques are complex porous structures with characteristic pore sizes. We interpret plaque morphology in the context of a new dynamical model based on competing aggregation and disaggregation processes in ki- netic steady-state equilibrium with an additional diffusion process allowing Ab deposits to diffuse over the surface of Plaques.
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characterization of the precursor protein of the non aβ component of Senile Plaques nacp in the human central nervous system
Journal of Neuropathology and Experimental Neurology, 1996Co-Authors: Michael C Irizarry, Megan J Mcnamara, Rudolph E Tanzi, Julia M George, David F Clayton, Bradley T HymanAbstract:A novel and highly conserved presynaptic protein has been independently described in rodents (synuclein/SYN1), songbirds (synelfin), and humans (the precursor protein of the non-Aβ component of Senile Plaques, NACP) ; a fragment of the latter has been detected in Senile Plaques in Alzheimer's disease (AD). We characterized the expression of NACP in human AD and non-AD brain. A subcellular fractionation study demonstrated that NACP was mainly localized to cytosolic fractions of human temporal cortex. NACP was also detectable in various membrane and vesicular fractions, suggesting that the protein was associated with membrane structures including synaptic vesicles. Pericellular immunostaining of the neuropil was observed in neocortical and limbic regions, supporting a synaptic localization. Senile Plaques in AD brains were not immunoreactive, and confocal microscopy suggested a loss of NACP immunoreactivity in cored Plaques. No difference was found in the amount of protein in AD and control frontal cortex, as measured by immunoblotting. PCR analysis showed that the full-length mRNA product was the major splice form in both AD and control human brains. Thus, despite the association of a hydrophobic fragment of NACP with Senile Plaques, our data suggest that the precursor itself is not a significant component of Plaques and NACP synthesis is not substantially altered in AD. Nevertheless, the protein is an abundant component of synaptic regions prone to degeneration in AD, and may have a role in the expression or advancement of the disease.
William R Markesbery - One of the best experts on this subject based on the ideXlab platform.
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copper iron and zinc in alzheimer s disease Senile Plaques
Journal of the Neurological Sciences, 1998Co-Authors: M A Lovell, J D Robertson, W J Teesdale, J L Campbell, William R MarkesberyAbstract:Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of Senile Plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P<0.05). Copper was significantly elevated (P<0.05) in the rim of SP compared with AD neuropil. Comparison of AD and control neuropil revealed a significant (P<0.05) elevation of Zn in AD subjects. The elevation of these elements in SP in AD is of interest in light of the observation that Cu, Fe and particularly Zn, can accelerate aggregation of amyloid beta peptide.
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Copper, iron and zinc in Alzheimer's disease Senile Plaques
Journal of the Neurological Sciences, 1998Co-Authors: M A Lovell, J D Robertson, W J Teesdale, J L Campbell, William R MarkesberyAbstract:Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of Senile Plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P
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Serum zinc, Senile Plaques, and neurofibrillary tangles: findings from the Nun Study.
Neuroreport, 1995Co-Authors: Christine L. Tully, David A. Snowdon, William R MarkesberyAbstract:ZINC appears to have a role in binding amyloid precursor protein in vitro, but it is not known whether zinc plays a role in Senile plaque formation in vivo in humans. Serum zinc concentrations were available from 12 sisters who died in the Nun Study, a longitudinal study of aging and Alzheimer's disease. Fasting serum zinc concentrations, determined approximately 1 year before death, showed moderate to strong negative correlations with Senile plaque counts in seven brain regions. In all brain regions combined, the age-adjusted negative correlations with serum zinc were statistically significant for total Senile Plaques and diffuse Plaques, and suggestive for neuritic Plaques. Thus serum zinc in the normal range may be associated with low Senile plaque counts in the elderly.
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cortical Senile Plaques in coronary artery disease aging and alzheimer s disease
Neurobiology of Aging, 1990Co-Authors: Larry D Sparks, John C Hunsaker, Stephen W Scheff, Richard J Kryscio, Jana L Henson, William R MarkesberyAbstract:Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). The cognitive change in AD has been correlated to the characteristic pathologic lesions in the brain, Senile Plaques (SP) and neurofibrillary tangles. Senile Plaques are the most consistent correlative marker in AD. We present preliminary data indicating that abundant SP are found in the brains of nondemented patients dying with or as a result of critical coronary artery disease (cCAD) compared to nonheart disease (non-HD) subjects; 15 of 20 cCAD patients contained SP and only two of 16 non-HD patients contained SP.
George Perry - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Proteins Present in Isolated Senile Plaques from Alzheimer’s Diseased Brains by MALDI-TOF MS with MS/MS
ACS Chemical Neuroscience, 2018Co-Authors: Andrea R. Kelley, George Perry, Stephan B. H. BachAbstract:The increase of insoluble Senile Plaques in the brain is a primary hallmark of Alzheimer’s disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of Senile Plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. Thirty-three components were reproducibly observed within tryptic aliquots of Senile Plaques from two different AD brains after sample preparation optimization. Additionally, this is one of the first accounts of LIFT being utilized for the direct sequencing of peptides from isolated Senile Plaques. While many of the species observed coisolated within Senile Plaques have been linked to AD etiology, if only speculatively, this is the first instance that many of them have been demonstrated to be a part of the Plaques themselves. This work is the first step in determining the potential roles that the species may have in the aggregation o...
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characterization of proteins present in isolated Senile Plaques from alzheimer s diseased brains by maldi tof ms with ms ms
ACS Chemical Neuroscience, 2018Co-Authors: Andrea R. Kelley, George Perry, Stephan B. H. BachAbstract:The increase of insoluble Senile Plaques in the brain is a primary hallmark of Alzheimer’s disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of Senile Plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. Thirty-three components were reproducibly observed within tryptic aliquots of Senile Plaques from two different AD brains after sample preparation optimization. Additionally, this is one of the first accounts of LIFT being utilized for the direct sequencing of peptides from isolated Senile Plaques. While many of the species observed coisolated within Senile Plaques have been linked to AD etiology, if only speculatively, this is the first instance that many of them have been demonstrated to be a part of the Plaques themselves. This work is the first step in determining the potential roles that the species may have in the aggregation o...
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challenging the amyloid cascade hypothesis Senile Plaques and amyloid β as protective adaptations to alzheimer disease
Annals of the New York Academy of Sciences, 2004Co-Authors: Gemma Casadesus, George Perry, Atsushi Takeda, Mark A SmithAbstract:Abstract: Ever since their initial description over a century ago, Senile Plaques and their major protein component, amyloid-β, have been considered key contributors to the pathogenesis of Alzheimer disease. However, counter to the popular view that amyloid-β represents an initiator of disease pathogenesis, we herein challenge dogma and propose that amyloid-β occurs secondary to neuronal stress and, rather than causing cell death, functions as a protective adaptation to the disease. By analogy, individuals suffering from altitude sickness nearly always have elevated levels of hemoglobin. However, while hemoglobin is toxic to cells in culture and increased erythropoiesis at sea level can be deadly, it is clear that the increases in hemoglobin occurring at altitude are beneficial. Amyloid, like hemoglobin, may also be beneficial, in this case, following neuronal stress or disease. Although controversial, a protective function for amyloid-β is supported by all of the available literature to date and also explains why many aged individuals, despite the presence of high numbers of Senile Plaques, show little or no cognitive decline. With this in mind, we suspect that current therapeutic efforts targeted toward lowering amyloid-β production or removal of deposited amyloid-β will only serve to exacerbate the disease process.
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oxidative posttranslational modifications in alzheimer disease a possible pathogenic role in the formation of Senile Plaques and neurofibrillary tangles
Molecular and Chemical Neuropathology, 1996Co-Authors: Mark A Smith, Lawrence M Sayre, Vincent M Monnier, George PerryAbstract:The distinctive pathological lesions of Alzheimer disease (AD), Senile Plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of Senile Plaques and neurofibrillary tangles (NFT).
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plasma membrane fragility in dystrophic neurites in Senile Plaques of alzheimer s disease an index of oxidative stress
Acta Neuropathologica, 1995Co-Authors: Darja Praprotnik, P. L. Richey, Mark A Smith, Harry V Vinters, George PerryAbstract:This study presents evidence for plasma membrane abnormalities of the dystrophic neurites in Senile Plaques of Alzheimer's disease. We found that the plasma membranes of dystrophic neurites are more labile to fixation than those membranes of other cells of the Senile plaque or of normal neurites distant from Senile Plaques. Further, we found vesicles in the extracellular space adjacent to dystrophic neurites and similar to those within them, suggesting that the increased lability seen in our preparations may, in vivo, be associated with release of neuritic contents. Plasma membrane alterations may be critical to deposition of amyloid-β in Senile Plaques from the abundant β-protein precursor of dystrophic neurites. The consequences of altered membrane integrity, such as calcium influx, lipid peroxidation and free radical damage, could also be responsible for many of the pathological correlates of the disease.
M A Lovell - One of the best experts on this subject based on the ideXlab platform.
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copper iron and zinc in alzheimer s disease Senile Plaques
Journal of the Neurological Sciences, 1998Co-Authors: M A Lovell, J D Robertson, W J Teesdale, J L Campbell, William R MarkesberyAbstract:Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of Senile Plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P<0.05). Copper was significantly elevated (P<0.05) in the rim of SP compared with AD neuropil. Comparison of AD and control neuropil revealed a significant (P<0.05) elevation of Zn in AD subjects. The elevation of these elements in SP in AD is of interest in light of the observation that Cu, Fe and particularly Zn, can accelerate aggregation of amyloid beta peptide.
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Copper, iron and zinc in Alzheimer's disease Senile Plaques
Journal of the Neurological Sciences, 1998Co-Authors: M A Lovell, J D Robertson, W J Teesdale, J L Campbell, William R MarkesberyAbstract:Concentrations of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of Senile Plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurologically normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P
Stephan B. H. Bach - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Proteins Present in Isolated Senile Plaques from Alzheimer’s Diseased Brains by MALDI-TOF MS with MS/MS
ACS Chemical Neuroscience, 2018Co-Authors: Andrea R. Kelley, George Perry, Stephan B. H. BachAbstract:The increase of insoluble Senile Plaques in the brain is a primary hallmark of Alzheimer’s disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of Senile Plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. Thirty-three components were reproducibly observed within tryptic aliquots of Senile Plaques from two different AD brains after sample preparation optimization. Additionally, this is one of the first accounts of LIFT being utilized for the direct sequencing of peptides from isolated Senile Plaques. While many of the species observed coisolated within Senile Plaques have been linked to AD etiology, if only speculatively, this is the first instance that many of them have been demonstrated to be a part of the Plaques themselves. This work is the first step in determining the potential roles that the species may have in the aggregation o...
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characterization of proteins present in isolated Senile Plaques from alzheimer s diseased brains by maldi tof ms with ms ms
ACS Chemical Neuroscience, 2018Co-Authors: Andrea R. Kelley, George Perry, Stephan B. H. BachAbstract:The increase of insoluble Senile Plaques in the brain is a primary hallmark of Alzheimer’s disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of Senile Plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. Thirty-three components were reproducibly observed within tryptic aliquots of Senile Plaques from two different AD brains after sample preparation optimization. Additionally, this is one of the first accounts of LIFT being utilized for the direct sequencing of peptides from isolated Senile Plaques. While many of the species observed coisolated within Senile Plaques have been linked to AD etiology, if only speculatively, this is the first instance that many of them have been demonstrated to be a part of the Plaques themselves. This work is the first step in determining the potential roles that the species may have in the aggregation o...
