Zaretsky Dmitry V, Zaretskaia Maria V
Zarbio Laboratories, Chapel Hill, NC 27516, USA.
Curr Alzheimer Res. 2025;22(3):179-204. doi: 10.2174/0115672050381553250425062803.
The manuscript describes how the framework of the integrative hypothesis of Alzheimer's disease (AD) can be deciphered using existing experimental and clinical data. First, the analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies indicate a correlation between AD diagnosis and heightened cellular uptake of beta-amyloid. Since beta-amyloid must be taken up by cells to become toxic, its uptake rate correlates with neurodegeneration. Also, aggregation seeds cannot form extracellularly due to low beta-amyloid levels in interstitial fluid but can develop inside lysosomes. Consequently, the density of extracellular aggregates correlates positively with cellular amyloid uptake rate. The model, which ties both beta-amyloid cytotoxicity and aggregation to cellular uptake, accurately predicts AD diagnosis patterns in the population. Second, beta-amyloid enters cells through endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage and explains intracellular ion disturbances (including calcium overload) after exposure to extracellular beta-amyloid. The permeabilization is caused by channels formed in lysosomal membranes by some amyloid fragments produced by proteolysis of full-length beta-amyloid. Some membrane channels are large enough to leak cathepsins to the cytoplasm, causing necrosis or apoptosis. Also, local spikes of calcium cytosolic concentration due to calcium leakage from lysosomes can activate calpains, contributing to cell death. In surviving cells, accumulation of damaged lysosomes results in autophagy failure and slow mitochondrial recycling, promoting the production of reactive oxygen species and further cell damage. In this framework, AD's etiology is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization and the appearance of activated proteases in the cytoplasm. The correlation between AD diagnosis and the density of amyloid aggregates occurs because both amyloid cytotoxicity and extracellular aggregate formation stem from cellular amyloid uptake. To reflect key processes, we call this framework the Amyloid Degradation Toxicity Hypothesis of Alzheimer's Disease. It explains various phenomena and paradoxes associated with AD pathobiology across molecular, cellular, and biomarker levels. The hypothesis also highlights the limitations of current AD biomarkers and suggests new diagnostic and prognostic tools based on disease pathogenesis. Additionally, the framework identifies potential pharmacological targets for preventing disease progression.
该手稿描述了如何利用现有的实验和临床数据来解读阿尔茨海默病（AD）综合假说的框架。首先，对淀粉样蛋白生物标志物和稳定同位素标记动力学（SILK）研究的分析表明，AD诊断与β-淀粉样蛋白细胞摄取增加之间存在关联。由于β-淀粉样蛋白必须被细胞摄取才会变得有毒，其摄取速率与神经退行性变相关。此外，由于间质液中β-淀粉样蛋白水平较低，聚集种子无法在细胞外形成，但可在溶酶体内发展。因此，细胞外聚集体的密度与细胞淀粉样蛋白摄取速率呈正相关。该模型将β-淀粉样蛋白的细胞毒性和聚集与细胞摄取联系起来，准确预测了人群中的AD诊断模式。其次，β-淀粉样蛋白通过内吞作用进入细胞。内吞的β-淀粉样蛋白诱导溶酶体通透性增加，这一过程在没有质膜损伤的情况下发生，并解释了暴露于细胞外β-淀粉样蛋白后细胞内离子紊乱（包括钙超载）的现象。通透性增加是由全长β-淀粉样蛋白经蛋白水解产生的一些淀粉样蛋白片段在溶酶体膜上形成的通道所致。一些膜通道足够大，可使组织蛋白酶泄漏到细胞质中，导致坏死或凋亡。此外，由于溶酶体钙泄漏导致的细胞质钙浓度局部峰值可激活钙蛋白酶，导致细胞死亡。在存活的细胞中，受损溶酶体的积累导致自噬失败和线粒体再循环缓慢，促进活性氧的产生并进一步损伤细胞。在此框架中，AD的病因是溶酶体中产生的淀粉样蛋白片段形成膜通道。发病机制包括溶酶体通透性增加和细胞质中活化蛋白酶的出现。AD诊断与淀粉样聚集体密度之间的相关性出现是因为淀粉样蛋白的细胞毒性和细胞外聚集体形成均源于细胞淀粉样蛋白摄取。为了反映关键过程，我们将此框架称为阿尔茨海默病的淀粉样蛋白降解毒性假说。它解释了在分子、细胞和生物标志物水平上与AD病理生物学相关的各种现象和矛盾。该假说还突出了当前AD生物标志物的局限性，并基于疾病发病机制提出了新的诊断和预后工具。此外，该框架确定了预防疾病进展的潜在药理学靶点。
