Kusakari Shinya, Nawa Mikiro, Hashimoto Yuichi, Matsuoka Masaaki
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo 160-8402, Japan.
Transl Neurosci. 2022 Feb 2;13(1):11-19. doi: 10.1515/tnsci-2022-0209. eCollection 2022 Jan 1.
Calmodulin-like skin protein (CLSP) inhibits Alzheimer's disease (AD)-related neurotoxicity. The activity of CLSP is reduced in AD. To restore the CLSP activity, we developed a hybrid peptide named CLSPCOL, consisting of CLSP(1-61) and the collagen-homologous region (COL) of adiponectin. It was previously shown that the CLSPCOL-mediated restoration of the reduced CLSP activity alleviated memory impairment and neuronal synaptic loss in double transgenic mice (APP/PS1 mice) at an advanced phase. Here, we examined whether CLSPCOL is effective against the memory impairment of the APP/PS1 mice at an early phase, and the memory impairment, caused by the temporal disturbance of the cholinergic neurotransmission, that mimics a part of AD-linked neuronal abnormality. The CLSPCOL-mediated restoration of the CLSP activity corrected the impairment in acquisition of fear-conditioned memory at an early-phase AD model. A single subcutaneous injection of CLSPCOL rescued the short-term working memory impairment, caused by subcutaneous injection of scopolamine. We have concluded that CLSPCOL is a promising disease-modifying therapeutic agent for not only the advanced phase but also the early-phase AD. It also serves as a symptomatic modifier of AD by potentiating the cholinergic neurotransmission.
类钙调蛋白样皮肤蛋白（CLSP）可抑制阿尔茨海默病（AD）相关的神经毒性。在AD中CLSP的活性会降低。为了恢复CLSP的活性，我们开发了一种名为CLSPCOL的杂合肽，它由CLSP（1 - 61）和脂联素的胶原同源区域（COL）组成。先前的研究表明，CLSPCOL介导的CLSP活性恢复可在晚期缓解双转基因小鼠（APP/PS1小鼠）的记忆障碍和神经元突触损失。在此，我们研究了CLSPCOL在早期是否对APP/PS1小鼠的记忆障碍有效，以及对由胆碱能神经传递的短暂干扰引起的、模拟部分AD相关神经元异常的记忆障碍是否有效。在早期AD模型中，CLSPCOL介导的CLSP活性恢复纠正了恐惧条件记忆获取方面的损伤。单次皮下注射CLSPCOL挽救了由皮下注射东莨菪碱引起的短期工作记忆损伤。我们得出结论，CLSPCOL不仅是晚期AD，也是早期AD一种有前景的疾病修饰治疗剂。它还通过增强胆碱能神经传递作为AD的症状改善剂。
