Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition.
Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition.
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DOI：
10.1523/jneurosci.3088-11.2011
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发表时间：
2011-10-12
期刊：
影响因子：
--
通讯作者：
Jucker M
中科院分区：
文献类型：
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作者：
Langer F;Eisele YS;Fritschi SK;Staufenbiel M;Walker LC;Jucker M
向年轻的β-淀粉样前体蛋白(APP)转基因小鼠脑内注射少量含有致病Aβ的脑提取物可外源性诱导脑β淀粉样变性及相关病理改变。脑提取液中可能的β-淀粉样蛋白诱导因子已被确定为一种聚集的Aβ，它是在体内以其最有效的构象或成分产生的。在这里，我们报告了脑提取液中的Aβ比合成纤维蛋白Aβ更耐蛋白水解酶K-(PK)，并且脑提取液中这种抗PK的部分在年轻的、预沉积的APP23转基因小鼠脑内注射时仍具有诱导β-淀粉样蛋白沉积的能力。脑提取液超速离心后，只有不到0.05%的A-β残留在上清液中，这些可溶性A-β主要对PK敏感。然而，在脑内注射时，这种可溶部分占未分离提取物观察到的β-淀粉样蛋白诱导的30%。延长超声破碎Aβ种子增加了脑提取液的种子容量。综上所述，这些结果表明，具有不同PK敏感性的多个Aβ组件能够在体内诱导β-淀粉样蛋白聚集。小而易溶的A-β种子是脑β-淀粉样变性的有效诱因，这一发现增加了这种种子可能介导β-淀粉样变性在大脑中传播的可能性。如果它们能够在体内被识别，体液中的可溶性Aβ种子也可以作为大脑β-淀粉样变和最终阿尔茨海默病S病的早期生物标记物。
Cerebral β-amyloidosis and associated pathologies can be exogenously induced by the intracerebral injection of small amounts of pathogenic Aβ-containing brain extract into young β-amyloid precursor protein (APP) transgenic mice. The probable β-amyloid-inducing factor in the brain extract has been identified as a species of aggregated Aβ that is generated in its most effective conformation or composition in vivo. Here we report that Aβ in the brain extract is more proteinase K- (PK) resistant than is synthetic fibrillar Aβ, and that this PK-resistant fraction of the brain extract retains the capacity to induce β-amyloid deposition upon intracerebral injection in young, pre-depositing APP23 transgenic mice. After ultra-centrifugation of the brain extract, less than 0.05% of the Aβ remained in the supernatant fraction, and these soluble Aβ species were largely PK-sensitive. However, upon intracerebral injection, this soluble fraction accounted for up to 30% of the β-amyloid induction observed with the un-fractionated extract. Fragmentation of the Aβ seeds by extended sonication increased the seeding capacity of the brain extract. In summary, these results suggest that multiple Aβ assemblies, with various PK sensitivities, are capable of inducing β-amyloid aggregation in vivo. The finding that small and soluble Aβ seeds are potent inducers of cerebral β-amyloidosis raises the possibility that such seeds may mediate the spread of β-amyloidosis in the brain. If they can be identified in vivo, soluble Aβ seeds in bodily fluids also could serve as early biomarkers for cerebral β-amyloidogenesis and eventually Alzheimer´s disease.