The receptor for advanced glycation end products (RAGE) is considered to contribute to the pathogenesis of Alzheimer's disease (AD), mediating amyloid beta (Aβ) accumulation, mitochondrial damage, and neuroinflammation. Previously, we have synthesized small peptides corresponding to the fragments (60–76) (P1) and (60–62) (P2) of the RAGE extracellular domain, and have shown that administration of P1 fragment but not P2 results in restoration of the spatial memory and decreases the brain Aβ (1–40) level in olfactory bulbectomized (OBX) mice demonstrating main features of Alzheimer's type neurodegeneration. In the present study, we have investigated the supposed mechanism of the therapeutic efficacy of P1 RAGE fragment and compared it to P2 short fragment. We have found that P1 restored activities of the respiratory chain in the Complexes I and IV in both cortical and hippocampal mitochondria of the OBX mice while P2 had no effect. Besides, fluorescein-labeled analog Flu-P1 bound to Aβ (1–40) and Aβ (1–42) with high affinity (K_d in the nanomolar range) whereas Flu-P2 revealed low affinity with tenfold higher K_d value for Aβ (1–40) and did not bind to Aβ (1–42). However, neither of the peptides had a notable impact on inflammation, estimated as mRNA expression of proinflammatory cytokines in the brain tissues of OBX mice. Taken together, our results suggest that direct Aβ-P1 interaction is one of the molecular events mediating the protection of the mitochondria in OBX animals from Aβ toxic effect. The RAGE fragment P1 would be the soluble decoy for Aβs and serve as a promising therapeutic agent against neurodegeneration accompanied by mitochondrial dysfunction.

晚期糖基化终产物 (RAGE) 受体被认为有助于阿尔茨海默病 (AD) 的发病机制，介导淀粉样蛋白 β (Aβ) 的积累、线粒体损伤和神经炎症。以前，我们已经合成了与 RAGE 胞外域的片段 (60–76) (P1) 和 (60–62) (P2) 相对应的小肽，并且已经表明施用 P1 片段而不是 P2 导致恢复空间记忆并降低嗅球切除 (OBX) 小鼠的大脑 Aβ (1-40) 水平，表明阿尔茨海默氏症型神经变性的主要特征。在本研究中，我们研究了 P1 RAGE 片段治疗功效的假设机制，并将其与 P2 短片段进行了比较。我们发现 P1 恢复了 OBX 小鼠皮质和海马线粒体中复合物 I 和 IV 中呼吸链的活性，而 P2 没有影响。此外，荧光素标记的类似物 Flu-P1 以高亲和力 (K_d在纳摩尔范围内），而 Flu-P2 显示出低亲和力，对 Aβ（1-40）的K _d值高十倍，并且不与 Aβ 结合（1-42）。然而，根据 OBX 小鼠脑组织中促炎细胞因子的 mRNA 表达估计，这两种肽都对炎症没有显着影响。总之，我们的结果表明直接 Aβ-P1 相互作用是介导保护 OBX 动物线粒体免受 Aβ 毒性作用的分子事件之一。RAGE 片段 P1 将是 Aβ 的可溶性诱饵，并作为一种有前途的治疗剂，用于对抗伴随线粒体功能障碍的神经变性。