Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.
Restoration of the reduced CLSP activity alleviates memory impairment in Alzheimer disease.
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CLSP活性降低的恢复可减轻阿尔茨海默病的记忆损伤。
DOI：
10.1038/s41398-020-01168-8
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发表时间：
2021-01-13
影响因子：
6.8
通讯作者：
Matsuoka M
中科院分区：
文献类型：
--
作者：
Hashimoto Y;Kusakari S;Nawa M;Okamoto K;Toyama Y;Matsuoka M
钙调素样皮肤蛋白（CLSP）是一种分泌肽，可抑制基于细胞的阿尔茨海默病（AD）模型中的神经元死亡，CLSP基因的转基因过表达可抑制AD模型小鼠（APP/PS1双转基因小鼠）中的突触丢失和记忆障碍。尽管CLSP作为AD抑制因子的预期作用，但CLSP活性不足是否与AD发病机制有关仍是未知数。在这项研究中，我们首先表明，脂联素，CLSP增效剂/保护剂，占主导地位的决定CLSP活性在中枢神经系统中有足够的浓度的CLSP，更高浓度的CLSP抑制剂，如载脂蛋白E，和脂联素的浓度较小。我们接下来表明，在AD患者和APP/PS1小鼠中，脑脂联素水平和神经元内SH 3BP 5水平（CLSP信号的重要效应物）均降低。最后，通过皮下注射由CLSP（1-61）和脂联素的胶原同源区组成的名为CLSPCOL的杂合肽来恢复CLSP活性，所述杂合肽具有比CLSP更有效的神经保护活性，对CLSP抑制剂的抑制不敏感，并且被有效地募集到脑中，减轻老年APP/PS1小鼠中的痴呆和突触丧失。总的来说，这些结果表明，可能由脂联素水平降低引起的CLSP活性降低导致AD脑中神经元免受神经毒性的保护不足，并且CLSP活性的恢复是治疗AD的有希望的策略。
Calmodulin-like skin protein (CLSP), a secreted peptide, inhibits neuronal death in cell-based Alzheimer’s disease (AD) models and transgenic overexpression of the CLSP gene suppresses synaptic loss and memory impairment in AD model mice, APPswe/PS1dE9 double transgenic mice (APP/PS1 mice). Despite the anticipated role of CLSP as an AD-suppressing factor, it remains unanswered whether the insufficiency of the CLSP activity is linked to the AD pathogenesis. In this study, we first show that adiponectin, a CLSP potentiator/protector, dominantly determines the CLSP activity in the central nervous system where there are sufficient concentrations of CLSP, higher concentrations of CLSP inhibitors such as apolipoprotein E, and smaller concentrations of adiponectin. We next show that both the levels of brain adiponectin and the intraneuronal levels of SH3BP5, an important effector of the CLSP signal, are reduced in both AD patients and APP/PS1 mice. Finally, the restoration of the CLSP activity by subcutaneous injection of a hybrid peptide named CLSPCOL consisting of CLSP(1-61) and the collagen-homologous region of adiponectin, which has more potent neuroprotective activity than CLSP, is insensitive to the suppression by the CLSP inhibitors, and is efficiently recruited into brains, alleviates dementia and synaptic loss in the aged APP/PS1 mice. Collectively, these results suggest that the reduction in the CLSP activity, likely caused by the reduction in the levels of adiponectin, leads to the insufficient protection of neurons from neurotoxicity in the AD brains and the restoration of the CLSP activity is a promising strategy for the treatment of AD.
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影响因子：
2.6
作者：
Matsui Y;Satoh K;Miyazaki T;Shirabe S;Atarashi R;Mutsukura K;Satoh A;Kataoka Y;Nishida N
通讯作者：
Nishida N
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Niikura T;Sidahmed E;Hirata-Fukae C;Aisen PS;Matsuoka Y
通讯作者：
Matsuoka Y
影响因子：
4.8
作者：
Hwang, Joonsung;Kalinin, Alexandr;Morasso, Maria I.
通讯作者：
Morasso, Maria I.
影响因子：
11
作者：
Chiba, T.;Yamada, M.;Aiso, S.
通讯作者：
Aiso, S.