淀粉样蛋白的降解产物：它们是罪魁祸首吗？

Title:Degradation Products of Amyloid Protein: Are They The Culprits?

Volume: 17 Issue: 10

关键词: 膜通道，β-淀粉样蛋白，神经毒性，蛋白质降解，阿尔茨海默氏病，脂质体。

摘要: Objectives: Beta-amyloid (Aβ) peptides are most toxic to cells in oligomeric form. It is commonly accepted that oligomers can form ion channels in cell membranes and allow calcium and other ions to enter cells. The activation of other mechanisms, such as apoptosis or lipid peroxidation, aggravates the toxicity, but it itself can result from the same initial point, that is, ion disturbance due to an increased permeability of membranes. However, experimental studies of membrane channels created by Aβ are surprisingly limited.

Methods: Here, we report a novel flow cytometry technique which can be used to detect increased permeability of membranes to calcium induced by the exposure to amyloid peptides. Calcium entry into the liposome is monitored using calcium-sensitive fluorescent probe. Undamaged lipid membranes are not permeable to calcium. Liposomes that are prepared in a calcium-free medium become able to accumulate calcium in a calcium-containing medium only after the formation of channels.

Results: Using this technique, we demonstrated that the addition of short amyloid fragment Ab25-35, which is known for its extreme toxicity on cultured neurons, readily increased membrane permeability to calcium. However, neither similarly sized peptide Ab22-35 nor full-length peptide Aβ1-42 were producing channels. The formation of channels was observed in the membranes made of phosphatidylserine, a negatively charged lipid, but not in membranes made of the neutral phosphatidylcholine.

Discussion: We have analyzed several issues which could be critical for understanding the pathogenesis of Alzheimer’s disease, specifically 1) the need for a negatively charged membrane to produce the ion channel; 2) the potential role of the aggregated form in cellular toxicity of Aβ peptides; 3) channelforming ability of multiple degradation products of amyloid; 4) non-specificity of ion channels formed by amyloid peptides. Potential targets of channel-forming oligomers appear to be intracellular and are organelles well-known for dysfunction in Alzheimer’s disease (mitochondria and lysosomes). In fact, lysosomes can also be the producers of degraded amyloid. Provided speculations support the hypothesis that neuronal toxicity can be caused by the degradation products of beta-amyloid.

Cite this article as:

Degradation Products of Amyloid Protein: Are They The Culprits?, Current Alzheimer Research 2020; 17 (10) . https://dx.doi.org/10.2174/1567205017666201203142103

DOI https://dx.doi.org/10.2174/1567205017666201203142103	Print ISSN 1567-2050
Publisher Name Bentham Science Publisher	Online ISSN 1875-5828