Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
Department of Neurology, Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan.
Transl Psychiatry. 2021 Jan 13;11(1):44. doi: 10.1038/s41398-020-01168-8.
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.
钙调蛋白样皮肤蛋白（CLSP）是一种分泌型肽，可抑制基于细胞的阿尔茨海默病（AD）模型中的神经元死亡，并且 CLSP 基因的转基因过表达可抑制 AD 模型小鼠（APPswe/PS1dE9 双转基因小鼠，APP/PS1 小鼠）中的突触损失和记忆障碍。尽管 CLSP 作为 AD 抑制因子的作用已得到预期，但 CLSP 活性不足是否与 AD 发病机制有关仍未得到解答。在这项研究中，我们首先表明，脂联素是 CLSP 的增效剂/保护剂，在中枢神经系统中（CLSP 浓度足够高，CLSP 抑制剂如载脂蛋白 E 的浓度更高，而脂联素的浓度更小），脂联素主导着 CLSP 的活性。接下来，我们发现 AD 患者和 APP/PS1 小鼠的大脑脂联素水平和 CLSP 信号的重要效应物 SH3BP5 的神经元内水平均降低。最后，通过皮下注射一种名为 CLSPCOL 的杂合肽（由 CLSP（1-61）和脂联素的胶原同源区组成）来恢复 CLSP 活性，这种杂合肽具有比 CLSP 更强的神经保护活性，对 CLSP 抑制剂的抑制作用不敏感，并且能有效地被募集到大脑中，从而减轻老年 APP/PS1 小鼠的痴呆和突触损失。总之，这些结果表明，CLSP 活性的降低可能是由于脂联素水平降低所致，导致 AD 大脑中的神经元无法充分免受神经毒性的侵害，而恢复 CLSP 活性是治疗 AD 的一种有前途的策略。
