Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Faculty Hospital, 140 59 Prague, Czech Republic.
Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, 100 34 Prague, Czech Republic.
Int J Mol Sci. 2024 Sep 7;25(17):9689. doi: 10.3390/ijms25179689.
The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ.
淀粉样蛋白级联假说假定，细胞外淀粉样β（Aβ）沉积是导致阿尔茨海默病（AD）的主要和初始原因，其特征为细胞内神经原纤维缠结；然而，直到现在，该机制的细节仍未被完全描述。我们的初步数据来自于日常神经病理学实践，表明过度磷酸化的 tau 蛋白的主要位置在营养不良神经突的细胞膜附近。这一观察结果启发我们提出了一个假设，即假定低密度脂蛋白受体相关蛋白 1（LRP1）与纤维状聚集物之间存在相互作用，特别是锚定在神经突斑块外围的 Aβ，使 LRP1-Aβ 复合物的内化变得不可行，从而导致膜功能障碍，导致以 tau 蛋白细胞内积累和过度磷酸化为特征的 tau 病。将 AD 理解为一种膜功能障碍性 tau 病，可能会引起人们对新的治疗方法的关注，这些方法不仅针对 Aβ 的产生，而且可能具有矛盾性地，预防 LRP1-Aβ 的形成。
