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）是一种分泌肽，可抑制基于细胞的阿尔茨海默氏病（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APPswe / PS1dE9的突触丢失和记忆障碍双转基因小鼠（APP / PS1小鼠）。尽管CLSP作为AD抑制因子发挥了预期的作用，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，我们首先显示脂联素（一种CLSP增强剂/保护剂）在中枢神经系统中具有决定性的作用，其中存在足够的CLSP浓度，较高浓度的CLSP抑制剂（例如载脂蛋白E）和较小浓度的脂联素。接下来我们表明，AD患者和APP / PS1小鼠的脑脂联素水平和神经内神经元SH3BP5（CLSP信号的重要效应物）水平均降低。最后，通过皮下注射由CLSP（1-61）和脂联素的胶原同源区域组成的杂种肽CLSPCOL来恢复CLSP活性，该肽比CLSP具有更强的神经保护活性，对CLSP抑制剂的抑制不敏感，并有效地招募入大脑，减轻老年APP / PS1小鼠的痴呆症和突触丧失。总的来说，这些结果表明CLSP活性的降低可能是由脂联素水平的降低引起的，导致神经元对AD脑的神经毒性的保护作用不足，而CLSP活性的恢复是一种有希望的策略。 AD的治疗。并有效地招募入大脑，减轻老年APP / PS1小鼠的痴呆症和突触丧失。总的来说，这些结果表明，CLSP活性的降低可能是由脂联素水平的降低引起的，导致神经元对AD脑神经元的保护作用不足，并且恢复CLSP活性是一种有希望的策略。 AD的治疗。并有效地招募入大脑，减轻老年APP / PS1小鼠的痴呆症和突触丧失。总的来说，这些结果表明，CLSP活性的降低可能是由脂联素水平的降低引起的，导致神经元对AD脑神经元的保护作用不足，并且恢复CLSP活性是一种有希望的策略。 AD的治疗。