D'Andrea M R, Nagele R G
Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
Biotech Histochem. 2010 Apr;85(2):133-47. doi: 10.3109/10520290903389445.
The details of the sequence of pathological events leading to neuron death in Alzheimer's disease (AD) are not known. Even the formation of amyloid plaques, one of the major histopathological hallmarks of AD, is not clearly understood; both the origin of the amyloid and the means of its deposition remain unclear. It is still widely considered, however, that amyloid plaques undergo gradual growth in the interstitial space of the brain via continual extracellular deposition of amyloid beta peptides at "seeding sites," and that these growing plaques encroach progressively on neurons and their axons and dendritic processes, eventually leading to neuronal death. Actually, histopathological evidence to support this mechanism is sparse and of uncertain validity. The fact that the amyloid deposits in AD brains that are collectively referred to as plaques are of multiple types and that each seems to have a different origin often is overlooked. We have shown experimentally that many of the so-called "diffuse amyloid plaques," which lack associated inflammatory cells, are either the result of leaks of amyloid from blood vessels at focal sites of blood-brain barrier breaches or are artifacts resulting from grazing sections through the margins of dense core plaques. In addition, we have provided experimental evidence that neuronal death via necrosis leaves a residue that takes the form of a spheroid "cloud" of amyloid, released by cell lysis, surrounding a dense core that often contains neuronal nuclear material. Support for a neuronal origin for these "dense core amyloid plaques" includes their ability to attract inflammatory cells (microglia and immigrant macrophages) and that they contain nuclear and cytoplasmic components that are somewhat resistant to proteolysis by lysosomes released during neuronal cell lysis. We discuss here the clinical and therapeutic importance of recognizing that amyloid deposition occurs both within neurons (intracellular) and in the interstitial (extracellular) space of the brain. For dense core plaques, we propose that the latter location largely follows from the former. This scenario suggests that blocking intraneuronal amyloid deposition should be a primary therapeutic target. This strategy also would be effective for blocking the gradual compromise of neuronal function resulting from this intraneuronal deposition, and the eventual death and lysis of these amyloid-burdened neurons that leads to amyloid release and the appearance of dense core amyloid plaques in the interstitium of AD brains.
导致阿尔茨海默病（AD）神经元死亡的病理事件序列细节尚不清楚。即使是淀粉样斑块的形成，这是AD主要的组织病理学特征之一，也未被完全理解；淀粉样蛋白的起源及其沉积方式仍不清楚。然而，人们仍然普遍认为，淀粉样斑块通过淀粉样β肽在“种子位点”持续的细胞外沉积在脑间质空间中逐渐生长，并且这些不断生长的斑块逐渐侵蚀神经元及其轴突和树突过程，最终导致神经元死亡。实际上，支持这一机制的组织病理学证据稀少且有效性存疑。AD大脑中被统称为斑块的淀粉样沉积物有多种类型且每种似乎都有不同起源这一事实常常被忽视。我们通过实验表明，许多缺乏相关炎症细胞的所谓“弥漫性淀粉样斑块”，要么是血脑屏障破裂局部位点血管中淀粉样蛋白泄漏的结果，要么是穿过致密核心斑块边缘的擦过切片产生的假象。此外，我们提供了实验证据，即通过坏死导致的神经元死亡会留下一种残留物，其形式为细胞裂解释放的淀粉样蛋白的球状“云”，围绕着通常包含神经元核物质的致密核心。对这些“致密核心淀粉样斑块”源于神经元的支持包括它们吸引炎症细胞（小胶质细胞和迁移巨噬细胞）的能力，以及它们包含对神经元细胞裂解过程中释放的溶酶体蛋白水解有一定抗性的核和细胞质成分。我们在此讨论认识到淀粉样沉积既发生在神经元内（细胞内）又发生在脑间质（细胞外）空间的临床和治疗重要性。对于致密核心斑块，我们提出后者的位置很大程度上源于前者。这种情况表明，阻断神经元内淀粉样沉积应是主要的治疗靶点。该策略对于阻断由这种神经元内沉积导致的神经元功能逐渐受损，以及这些负载淀粉样蛋白的神经元最终死亡和裂解从而导致淀粉样蛋白释放和AD大脑间质中致密核心淀粉样斑块出现也将是有效的。
