Peptide Compositions of the Cerebrovascular and Senile Plaque Core Amyloid Deposits of Alzheimer′s Disease

Miller, David L.; Papayannopoulos, Ioannis A.; Styles, J.; Bobin, S.; Lin, Yuchen; Biemann, K.; Iqbal, Khalid

doi:10.1006/abbi.1993.1112

Cited by 456 publications

(361 citation statements)

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“…Abundant experimental data indicated that the major component of the plaques in AD patient's brain is ␤-peptides, which aggregate into amyloid fibrils with cross-␤-structure (2,23,24). An essential question concerning the plaques is the origin of the amyloid fibrils formation.…”

Section: Discussionmentioning

confidence: 99%

“…The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2)(3)(4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4)(5)(6).…”

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confidence: 99%

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Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

242

259

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The amyloid ␤-peptides (A␤s), containing 39 -43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A␤40, 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an ␣-helix to ␤-sheet conformational transition for A␤40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with ␤-sheet components were observed as intermediates in the unfolding pathway of A␤40. Four glycines (G25, G29, G33, and G37) are important for A␤40 to form ␤-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the ␤-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A␤40 is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for A␤40 aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A␤ and amyloid fibril formation. molecular dynamics simulation A lzheimer's disease (AD), a neurodegenerative disorder, is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain (1). The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2-4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4-6). Recently, however, compelling evidence has emerged that not the fibrillar aggregates but the dominant ␤-sheet structure of oligomers and fibril intermediates (protofibrils) are neurotoxic and might be the determinant pathogenic factor in AD (7-9). For example, Walsh et al. (8) demonstrated that cerebral microinjection of cell medium containing abundant A␤ monomers and oligomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. The conflict between the amyloid hypothesis and these new emerging experimental observations has stimulated more and more researchers to study the earliest phases of A␤ assembly and to explore the intrinsic properties of A␤s and the conformational dynamic behaviors of the A␤ monomer (9-15).In addition, it has been established experimentally that the major secondary structure adopted by A␤ depends on the environment. The A␤ monomer favors an ␣-helix structure in a me...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Conformational transition of amyloid β-peptide

Shen

Luo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

242

259

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“…Heterogeneity of the amino terminus of A␤ peptides was also detected in the earliest purification of the ␤-amyloid plaque core (29). Interestingly, A␤2-39/40 is a major A␤ peptide species of cerebrovascular ␤-amyloid, which contains a higher relative amount of A␤2-x as compared with plaque core ␤-amyloid (68,69). Studies of the A␤ peptides secreted into the media of various cultured cells and cell lines transfected with differing APP constructs have also identified A␤2-x among other amino-terminal-truncated A␤ peptide species (7,70,71).…”

Section: Amino-terminal-and Carboxyl-terminal-truncated A␤ Species Inmentioning

confidence: 98%

Elevation of β-Amyloid Peptide 2–42 in Sporadic and Familial Alzheimer's Disease and Its Generation in PS1 Knockout Cells

Wiltfang¹,

Esselmann²,

Cupers³

et al. 2001

Journal of Biological Chemistry

118

123

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show a decrease of all secreted A␤ peptide species, as expected, because this mutant is processed mainly by ␣-secretase. This drop is even more pronounced for the APP-KK construct (APP mutant carrying an endoplasmic reticulum retention motif). Surprisingly, A␤2-42 is significantly less affected in PS1؊/؊ neurons and in neurons transfected with the endocytosis-deficient APP-⌬ct construct. Our data confirm that PS1 is closely involved in the production of A␤1-40/42 and the carboxyl-terminal-truncated A␤1-37, A␤1-38, and A␤1-39, but the amino-terminaltruncated and carboxyl-terminal-elongated A␤2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter A␤ peptide species could be generated by a ␤ Asp/Ala -secretase activity.

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“…In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4,7,8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11).…”

mentioning

confidence: 99%

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

189

225

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Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

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Peptide Compositions of the Cerebrovascular and Senile Plaque Core Amyloid Deposits of Alzheimer′s Disease

Cited by 456 publications

References 0 publications

Conformational transition of amyloid β-peptide

Conformational transition of amyloid β-peptide

Elevation of β-Amyloid Peptide 2–42 in Sporadic and Familial Alzheimer's Disease and Its Generation in PS1 Knockout Cells

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

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