アルツハイマー病のAβ1-42オリゴマーのトランスメブラン構造
Birgit Strodel1, Jason W L Lee, Christopher S Whittleston
1Institut für Strukturbiologie und Biophysik, Strukturbiochemie, Forschungszentrum Jülich, 52425 Jülich, Germany. b.strodel@fz-juelich.de
Journal of the American Chemical Society
|September 9, 2010
まとめ
アルツハイマー病のアミロイドβ-ペプチド (Aβ) オリゴーマーが膜に毛穴を形成する. 安定したAβ(1-42) 構造は,テトラメリックおよびヘクサメリックβシート亜単位がこれらの有毒な毛穴を形成することを示唆しています.
科学分野:
- バイオフィジックス 生物物理学
- コンピューティング・ケミストリー
- 神経科学は神経科学である.
背景:
- アルツハイマー病は,アミロイドβ-ペプチド (Aβ) オリゴーマーと関連しています.
- Aβオリゴマーは,膜孔形成を通じて神経毒性を引き起こすと仮定されています.
研究 の 目的:
- 膜環境におけるAβ(1-42) オリゴーマーをモデル化する.
- Aβ誘発の膜破壊と毒性の構造的基礎を解明する.
主な方法:
- 構造の識別のためのベースンホッピンググローバル最適化.
- パラレル・テンピリング・スキームとオリゴーマー生成手順の導入.
- 暗黙の脂質二重層におけるAβ ((1-42)) モノマーとオリゴマー (オクタマーまで) のモデリング.
主要な成果:
- 安定した,膜を横断するβシート構造をAβ(1-42) モノマーで特定した.
- ダイマーからヘクサマーまでのオーダーされたβシート構造を観察した.
- オクタマーが膜内で,固有の安定した四重体単位に分解することを発見した.
結論:
- Aβ毛穴は,テトラメリックおよびヘクサメリックβシートサブユニットで構成されることがあります.
- 提案されたAβ毛孔モデルは,実験的な生体物理学的および生化学的データと一致しています.
- アルツハイマー病のアミロイド毒性のメカニズムに関する構造的な洞察を提供します.
関連する概念動画
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
01:23Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
01:26Alzheimer's Disease: Overview
Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
01:22Dementia l: Introduction
Dementia is an acquired, progressive syndrome characterized by a decline in multiple cognitive domains severe enough to impair daily functioning and reduce independence. Although memory loss is a central feature, the diagnosis requires additional deficits involving language, executive function, visuospatial skills, judgment, calculation, or abstract reasoning. These cognitive impairments reflect underlying neurodegenerative or vascular processes that gradually disrupt neuronal networks...
01:29Alzheimer Disease l: Introduction
Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...