Oligomerization and Toxicity of β-Amyloid-42 Implicated in Alzheimer's Disease

El‐Agnaf, Omar M. A.; Mahil, Devinder S.; Patel, Bhroma P.; Austen, Brian

doi:10.1006/bbrc.2000.3051

Cited by 179 publications

(148 citation statements)

References 20 publications

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“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Amyloid is toxic when applied exogenously to or when formed within cultured cells. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Mouse and C. elegans models of amyloid diseases show that the cytotoxicity associated with amyloidogenesis increases with organismal age. 22,33 Postnuclear supernatant (PNS) from C. elegans has recently been shown to disaggregate Ab 1-40 amyloid fibrils, which are linked to Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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The formation of amyloid, a cross-b-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid b (Ab) 1-40 or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

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Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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“…For these reasons, we sought to identify a more sensitive assay for molecular discovery screening regimens that is a better representation of the early stages of oligomerization. The principle of the present study focuses on an ELISA-based capture assay for oligomer detection [35,36]. This ELISA format uses a single -specific mAb for both antigen capture and detection and is capable of clearly distinguishing monomeric peptide from oligomers.…”

Section: Discussionmentioning

confidence: 99%

“…This ELISA format uses a single -specific mAb for both antigen capture and detection and is capable of clearly distinguishing monomeric peptide from oligomers. Importantly for our objectives, this assay also discerns earlystage, low-molecular weight soluble aggregates from laterstage, amyloid fibrils [36], and in this manner is better suited to identify inhibitors of the most critical stage of peptide oligomerization.…”

Section: Discussionmentioning

confidence: 99%

“…Based upon previous methods developed by LeVine [35] and El-Agnaf [36], the sensitivity of this approach permits the use of sub-μM concentrations of peptide for initiation of the oligomerization reaction and more closely reflects amounts that can be expected in vivo. Most importantly, using lower peptide concentrations will focus inhibitor identification assays on the early stages of oligomer formation to more precisely target the most neurotoxic form of aggregates [36]. And finally, an ELISA-based approach should not only allow for more cost effective screening of large chemical libraries, but should also permit a more accurate assessment of peptide:inhibitor stoichiometry for future studies aimed at identifying mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

Gonzales¹,

Orlando²

2009

TOBIOTJ

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Amyloid deposits found in Alzheimer's disease result from aggregation of peptide which leads to loss of synaptic function, chronic microglial activation and cognitive impairment. Because of this, identification of small molecule inhibitors of aggregation as potential therapeutics is a topic of current interest. The majority of inhibitor screening approaches rely on in vitro assays that lack the necessary sensitivity to distinguish low-molecular weight oligomers from larger, more advanced-stage fibrillar structures. Differentiating between these two structures is of vital concern since recent studies indicate that small, early-stage oligomers are the most neurotoxic form of peptide aggregate. To address this limitation, we have explored the adaptability of a recently described ELISA-based assay for discovery of small molecule inhibitors of oligomerization. Results show that this assay is highly sensitive as it is able to quantify oligomers with as little as 80 nM input peptide. In addition, data were obtained re-confirming the function of curcumin as a potent inhibitor of aggregation (IC 50 = 2 μM) and defining its inhibitor:peptide functional stoichiometry. Further examination of other known anti-aggregation compounds showed that this assay is able to discriminate between inhibitors of early-stage, low-molecular weight oligomers and later-stage, high-molecular weight fibrillar structures. These findings indicate that this new ELISA-based assay is capable of identifying novel small molecule inhibitors that function during the initial stages of peptide assembly.

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“…Изучение состава сенильных бляшек мозга, образующихся при БА, показало, что их основными компонентами являются пептиды Аb40 и Аb42 [41]. Сравнительные исследования Аb40 и Аb42 в системах in vitro и in vivo показали, что Аb 42 гораздо быстрее агрегирует и обладает более высокой нейротоксичностью, чем Аb 40 [42][43][44][45][46]. Предполагается, что более высокая [47][48][49].…”

Section: ангиотензин превращающий фермент и болезнь альцгеймераunclassified

Angiotensin converting enzyme and Alzheimer's disease

Кугаевская

2013

BIOMED KHIM

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Болезнь Альцгеймера (БА) -неизлечимое дегенеративное заболевание центральной нервной системы, приводящее к деменции. В основе БА лежит нейродегенеративный процесс, приводящий к гибели нейронов коры головного мозга, связанный с образованием в мозге нейрофибриллярных клубков и отложением сенильных или амилоидных бляшек, главным компонентом которых является пептид бета-амилоид (Аb). Факторами риска развития БА являются возраст, а также гипертензия, атеросклероз, диабет и гиперхолестеринемия, в патогенез которых вовлечен ангиотензин превращающий фермент (АПФ), ключевой фермент ренин-ангиотензиновой (РАС) и калликреин-кининовой (ККС) систем. Недавно было обнаружено, что АПФ, наряду с другими металлопротеиназами, принимает участие в метаболизме Аb, расщепляя связи на N-концевом и С-концевом участках молекулы Аb. Интерес к роли АПФ в процессах деградации Аb связан с тем, что назначение ингибиторов АПФ (иАПФ) является основным терапевтическим подходом, применяемым при лечении различных форм гипертонии и других сердечно-сосудистых заболеваний. Однако до сих пор не решен вопрос о том, могут ли применяться антигипертензивные препараты, тормозящие РАС, для лечения или предупреждения БА. В настоящее время проводятся многочисленные исследования, посвященные поиску взаимосвязи между РАС и БА.Ключевые слова: болезнь Альцгеймера, пептид бета-амилоид, ангиотензин превращающий фермент, ингибиторы ангиотензин превращающего фермента.ВВЕДЕНИЕ. Болезнь Альцгеймера (БА) -один из наиболее распространенных случаев деменции, составляющий 50-60% от общего числа заболевших. Основным фактором риска развития БА является возраст. Число заболевших существенно растет после 65 лет и приближается к 50% среди людей, достигших 85 лет [1]. Хотя традиционно БА рассматривается 5

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Oligomerization and Toxicity of β-Amyloid-42 Implicated in Alzheimer's Disease

Cited by 179 publications

References 20 publications

Discovery and characterization of a mammalian amyloid disaggregation activity

Discovery and characterization of a mammalian amyloid disaggregation activity

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

Angiotensin converting enzyme and Alzheimer's disease

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