BETA-AMYLOID NEUROTOXICITY REQUIRES FIBRIL FORMATION AND IS INHIBITED BY CONGO RED
BETA-AMYLOID NEUROTOXICITY REQUIRES FIBRIL FORMATION AND IS INHIBITED BY CONGO RED
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DOI：
10.1073/pnas.91.25.12243
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发表时间：
1994-12-06
影响因子：
11.1
通讯作者：
YANKNER, BA
中科院分区：
文献类型：
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作者：
LORENZO, A;YANKNER, BA
β-淀粉样蛋白（β A）通常作为无毒的可溶性肽产生。在阿尔茨海默病中，β A在脑中聚集并积累为与神经退行性变化相关的惰性弥漫性斑块或致密斑块。为了确定神经毒性与β A物理状态的关系，我们创建了（i）与弥散斑类似的β A非淀粉样无定形聚集体[无定形β A（Am-beta A）]和（ii）与致密斑类似的β A淀粉样原纤维[纤维状β A（Fib-beta A）]。在原代大鼠海马培养中，Fib-beta A具有神经毒性，而Am-beta A没有毒性。Fib-beta A导致存活神经元中突触的显著损失，而Am-beta A对突触数量没有影响。淀粉样蛋白原纤维结合染料刚果红通过抑制原纤维形成或通过结合到预先形成的原纤维来抑制Fib-beta A神经毒性。刚果红还抑制糖尿病相关胰淀素（另一种淀粉样纤维）的胰岛细胞毒性。这些结果表明β A神经毒性需要原纤维形成。这些发现和我们以前的证明，胰淀素原纤维是有毒的，表明淀粉样蛋白原纤维的常见细胞病变效应可能有助于阿尔茨海默病和其他淀粉样变性的发病机制。
beta-Amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, we created (i) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (ii) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. These results indicate that beta A neurotoxicity requires fibril formation. These findings and our previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses.