Zhang Hua, Wu Lili, Pchitskaya Ekaterina, Zakharova Olga, Saito Takashi, Saido Takaomi, Bezprozvanny Ilya
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
J Neurosci. 2015 Sep 30;35(39):13275-86. doi: 10.1523/JNEUROSCI.1034-15.2015.
Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca(2+)/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2-nSOC-CaMKII pathway is downregulated in presenilin 1 M146V knock-in (PS1-M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular β-amyloid 42 in APPKI culture media. Our results indicate that extracellular Aβ42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca(2+) levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2-nSOC-CaMKII pathway causes loss of mushroom synaptic spines in both presenilin and APPKI mouse models of AD. We propose that modulators/activators of this pathway may have a potential therapeutic value for treatment of memory loss in AD. Significance statement: A direct connection between amyloid-induced synaptic mushroom spine loss and neuronal store-operated calcium entry pathway is shown. These results provide strong support for the calcium hypothesis of neurodegeneration and further validate the synaptic store-operated calcium entry pathway as a potential therapeutic target for Alzheimer's disease.
阿尔茨海默病（AD）是全球老年人痴呆最常见的病因。我们提出，AD中的记忆丧失与参与长期记忆存储的蘑菇状突触后棘的不稳定有关。我们先前证明，基质相互作用分子2（STIM2）调节的突触后棘中的神经元储存-操作性钙内流（nSOC）通过维持突触钙/钙调蛋白依赖性蛋白激酶II（CaMKII）的活性在蘑菇状棘的稳定性中起关键作用。此外，我们先前证明，在AD的早老素1 M146V基因敲入（PS1-M146V KI）小鼠模型中，STIM2-nSOC-CaMKII通路被下调，导致该模型中海马蘑菇状棘的丧失。在本研究中，我们证明在AD的淀粉样前体蛋白基因敲入（APPKI）小鼠模型中，海马蘑菇状突触后棘也会丧失。我们证明，蘑菇状棘的丧失是由于APPKI培养基中细胞外β-淀粉样蛋白42的积累所致。我们的结果表明，细胞外Aβ42通过过度激活APPKI神经元中的mGluR5受体起作用，导致内质网中钙水平升高、STIM2表达的代偿性下调、突触nSOC受损以及CaMKII活性降低。mGluR5的药理学抑制或STIM2的过表达挽救了突触nSOC，并防止了APPKI海马神经元中蘑菇状棘的丧失。我们的结果表明，突触STIM2-nSOC-CaMKII通路的下调导致了AD的早老素和APPKI小鼠模型中蘑菇状突触棘的丧失。我们提出，该通路的调节剂/激活剂可能对治疗AD中的记忆丧失具有潜在的治疗价值。意义声明：显示了淀粉样蛋白诱导的突触蘑菇状棘丧失与神经元储存-操作性钙内流途径之间的直接联系。这些结果为神经退行性变的钙假说提供了有力支持，并进一步验证了突触储存-操作性钙内流途径作为阿尔茨海默病潜在治疗靶点的有效性。
