The Aβ 3-Pyroglutamyl and 11-Pyroglutamyl Peptides Found in Senile Plaque Have Greater β-Sheet Forming and Aggregation Propensities in Vitro than Full-Length Aβ

He, Weilan; Barrow, Colin J.

doi:10.1021/bi990563r

Cited by 210 publications

(238 citation statements)

References 30 publications

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“…Additionally, A␤ pE3 is known to have a high aggregation propensity (54,55), increased stability (56), enhanced toxicity compared with fulllength A␤ (57), and dramatically reduced solubility at physiological pH-conditions (58). Our findings go along with the A␤ pE3 seeding hypothesis (20,54,57). Here, we further corroborate the importance of A␤ pE3-42 in the etiology of AD by demonstrating the effects of elevating A␤ pE3-42 in 5XFAD mice.…”

Section: Discussionsupporting

confidence: 81%

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam

Portelius

Zetterberg

et al. 2012

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 81%

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam

Portelius

Zetterberg

et al. 2012

Journal of Biological Chemistry

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“…In addition, the formation of the N-terminal pyroglutamate, which is resistant to degradation by peptidases, increases the stability of the peptide. He and Barrow (46) reported that A␤ pE3-x peptides show enhanced ␤-sheet formation and aggregation propensity in aqueous and hydrophobic media compared with full-length A␤. They suggested that the loss of three charged groups facilitates and stabilizes ␤-sheet formation by reducing the level of unfavorable charge repulsion between strands (46).…”

Section: Biochemical Properties Of Pyroglutamate A␤mentioning

confidence: 99%

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

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

195

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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“…A␤ peptides were synthesized using manual solid-phase Boc (N-tert-butoxycarbonyl) amino acid chemistry as previously described (He and Barrow, 1999). Peptides were cleaved from the resin using anhydrous hydrogen fluoride with p-cresol/pthiocresol as scavengers.…”

Section: Synthesis Of A␤ Peptidesmentioning

confidence: 99%

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

Postuma

Nunan

et al. 2000

Journal of Neurochemistry

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Accumulation of the ␤-amyloid protein (A␤) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism of A␤ toxicity remains unclear. A␤ can bind to the extracellular matrix, a structure that regulates adhesive events such as neurite outgrowth and synaptogenesis. The binding of A␤ to the extracellular matrix suggests that A␤ may disrupt cell-substrate interactions. Therefore, the effect of substrate-bound A␤ on the growth of isolated chick sympathetic and mouse cortical neurons was examined. A␤1-40 and A␤1-42 had dose-dependent effects on cell morphology. When tissue culture plates were coated with 0.1-10 ng/well A␤, neurite outgrowth increased. Higher amounts of A␤ peptides (Ն3 g/well) inhibited outgrowth. The inhibitory effect was related to aggregation of the peptide, as preincubation of A␤1-40 for 24 h at 37°C (a process known to increase amyloid fibril formation) was necessary for inhibition of neurite outgrowth. A␤29 -42, but not A␤1-28, also inhibited neurite outgrowth at high concentrations, demonstrating that the inhibitory domain is located within the hydrophobic C-terminal region. A␤1-40, A␤1-42, and A␤29 -42 also inhibited cell-substrate adhesion, indicating that the effect on neurite outgrowth may have been due to inhibition of cell adhesion. The results suggest that accumulation of A␤ may disrupt celladhesion mechanisms in vivo.

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The Aβ 3-Pyroglutamyl and 11-Pyroglutamyl Peptides Found in Senile Plaque Have Greater β-Sheet Forming and Aggregation Propensities in Vitro than Full-Length Aβ

Cited by 210 publications

References 30 publications

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

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

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

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