Lorenzo A, Yankner B A
Department of Neurology, Harvard Medical School, Boston, MA.
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12243-7. doi: 10.1073/pnas.91.25.12243.
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.
β-淀粉样蛋白（βA）通常作为一种无毒的可溶性肽产生。在阿尔茨海默病中，βA会聚集并在大脑中积累，形成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βA物理状态的关系，我们制备了（i）类似于弥漫性斑块的βA非淀粉样生成无定形聚集体[无定形βA（Am-βA）]和（ii）类似于致密斑块的βA淀粉样生成原纤维[原纤维βA（Fib-βA）]。在原代大鼠海马培养中，Fib-βA具有神经毒性，而Am-βA没有毒性。Fib-βA导致存活神经元中的突触显著丧失，而Am-βA对突触数量没有影响。淀粉样原纤维结合染料刚果红通过抑制原纤维形成或与预先形成的原纤维结合来抑制Fib-βA的神经毒性。刚果红还抑制了与糖尿病相关的胰岛淀粉样多肽（另一种淀粉样原纤维）对胰岛细胞的毒性。这些结果表明，βA神经毒性需要原纤维形成。这些发现以及我们之前证明胰岛淀粉样多肽原纤维具有毒性的结果表明，淀粉样原纤维的一种常见细胞病变效应可能导致阿尔茨海默病和其他淀粉样变性疾病的发病机制。
