Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET
Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET
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DOI：
10.1093/brain/awx057
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发表时间：
2017-05-01
期刊：
影响因子：
14.5
通讯作者：
Masters, Colin L.
中科院分区：
文献类型：
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作者：
Roberts, Blaine R.;Lind, Monica;Masters, Colin L.
我们将人类阿尔茨海默病患者和对照组的额叶皮质灰质分成四个生化定义的池，代表四个不同的隔室：可溶性/胞质，外周膜/囊泡货物，积分脂质/膜池和聚集/不溶性碎片。大多数容易提取的淀粉样蛋白-β仍然与脂质/膜隔室相关。在阿尔茨海默病中淀粉样蛋白-β（42）种类丢失的生化池之间存在淀粉样蛋白-β的交换，这与肽被不可逆地捕获在细胞外沉积物中一致。定量淀粉样蛋白-β数据，结合磁共振成像体积分析大脑中皮质灰质的量，使我们能够估计阿尔茨海默病（6.5 mg）和对照（1.7 mg）大脑中淀粉样蛋白-β的总质量。1.4的阈值正电子发射断层扫描标准摄取值比率等于5.0 kg淀粉样蛋白-β/g灰质，2.3的平均阿尔茨海默病痴呆标准摄取值比率水平等于11.20 kg淀粉样蛋白-β/g灰质。从正电子发射断层扫描标准摄取值的比值到阿尔茨海默病痴呆症观察到的平均值，淀粉样蛋白的积累需要19年。该积累时间窗结合阿尔茨海默病和对照脑之间4.8mg淀粉样蛋白-β的差异允许淀粉样蛋白-β积累的第一近似值为28 ng/h。这相当于总淀粉样蛋白-β产生的估计2-5%沉积为不溶性斑块。了解淀粉样蛋白-β积累的这些速率允许更定量的方法来靶向散发性阿尔茨海默病中淀粉样蛋白-β清除的失败。
We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-beta remains associated with a lipid/membranous compartment. There is an exchange of amyloid-beta between the biochemical pools that was lost for the amyloid-beta(42) species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-beta data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-beta in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 kg amyloid-beta/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 kg amyloid-beta/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8mg of amyloid-beta between Alzheimer's disease and control brain allows for a first approximation of amyloid-beta accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-beta production being deposited as insoluble plaques. Understanding these rates of amyloid-beta accumulation allows for a more quantitative approach in targeting the failure of amyloid-beta clearance in sporadic Alzheimer's disease.