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Extracellular
junk and how to get rid of it
细胞外垃圾及其排除
Extracellular
junk is different from extracellular cross-linking -- it means aggregates of
stuff that do not have any function (not even a biophysical one) and should
ideally have been destroyed, but have proven resistant to destruction. 细胞外垃圾与细胞外的交联键不同—细胞外垃圾意思是垃圾堆，没有任何功能（甚至没有生物物理功能），应当被清除干净，但是，已证明清除不了。 There
are two main examples of such junk. One is the acellular lipid core of mature
atherosclerotic plaques, but that doesn't really count, because macrophages
are constantly arriving and eating bits of that core, and the only problem is
that they can't then break it down after eating it, and eventually they die
and become part of the problem. 此类垃圾，有两个好例子。一是成熟的动脉粥样硬化斑块的非细胞脂质核，但是，这种脂质核并非真正脂质核心，因为巨噬细胞不断来吃掉一点这种核心，唯一的问题是它们吃后不能消化，它们最终死亡并成为该问题的一部分。 So
this would be completely fixed if we could make the intracellular degradation
machinery more powerful, as explained here. The other big
problem of extracellular junk is called amyloid. Amyloid forms into big
globules called plaques in the brain of Alzheimer's disease patients, and the
same thing happens (more slowly) in everyone's brains. 所以，如果我们能够使细胞内降解机器变得更强大[像在这里（here）解释的那样]，那么这个问题就能完全解决。细胞外垃圾的另一个大问题称为淀粉体。淀粉体在老年痴呆症病人的脑中形成很大的、称为斑块的小球，同样的事情也发生在每个人的脑中（较慢而已）。 We
don't actually yet know for sure that amyloid is what makes Alzheimer's
sufferers lose cognitive function, but we can be pretty sure that the plaques
aren't doing any good (though some researchers think that the individual
protein molecules do do some good before they aggregate into plaques), so to
be on the safe side we should try to get rid of them. 实际上我们并不确切知道，淀粉体是什么使得老年痴呆症患者失去认知功能，但我们可以确认，那些斑块没有做任何好事（虽然某些研究者认为，个体的蛋白质分子在它们聚集成斑块前做了一些好事），所以，为安全起见，我们应当尝试去清除它们。 The
same applies to a variety of similar aggregates that form in other tissues
during aging and age-related diseases, of which the best-known is islet
amyloid in type 2 diabetes. 同样的事情也适用于各种相似的堆积物，这些堆积物在老化和与年龄相关的疾病中，形成于其他的组织中，最熟知的是在II型糖尿病中的淀粉样小岛。 A
strategy for indefinitely postponing the accumulation of such material is
being pursued by Elan Pharmaceuticals: vaccination to stimulate the immune
system (specifically, microglia) to engulf the material. When it has been
internalised, it may still be resistant to degradation, but if so its
degradation can be achieved by the approach necessary for naturally
intracellular aggregates described here. The early clinical
trials of the Elan vaccine had to be stopped prematurely because of
side-effects, but they're working on a better vaccine. 长期延缓这种物质积累的策略，由埃兰制药公司（Elan Pharmaceuticals）着手进行：接种疫苗来刺激免疫系统（特异名称为小神经胶质细胞）、来吞噬这种物质。它被吞噬时，它仍然可以抗拒降解，如果这样，它的降解可以由在这里（here）描述的为天然细胞内堆积物所必需的方法来解决。由于副作用太大，埃兰（Elan）疫苗的早期临床试验不得不提前停止，但是，他们正在研制更好的疫苗。 Another
strategy is to use small molecules to dissolve the plaques. It seems that the
surface of the plaque can be disrupted by small peptides that winkle their
way into it, and this makes it less stable, so whole protein molecules float
off the surface. These small peptides are called beta-breakers. 另一个策略是用小分子物质来溶解斑块。斑块的表面似乎可被能开路进入斑块的小肽所破坏，使得斑块不大稳定，这样，整个蛋白质分子就飘落斑块。这些小肽被称为β-破碎机。 Talks
on this topic at IABG 10: 以此题目在IABG 10讲话：Nitsch |
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