Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Anesthesiology and Intensive Care, Technische Universität München, Munich 81675, Germany.
Neurobiol Dis. 2019 Apr;124:489-504. doi: 10.1016/j.nbd.2018.12.022. Epub 2018 Dec 27.
There is evidence that cognitive decline in Alzheimer's disease (AD) results from deficiencies in synaptic communication (e.g., loss of mushroom-shaped 'memory spines') and neurodegenerative processes. This might be treated with sigma-1 receptor (S1R) agonists, which are broadly neuroprotective and modulate synaptic plasticity. For example, we previously found that the mixed muscarinic/S1R agonist AF710B prevents mushroom spine loss in hippocampal cultures from APP knock-in (APP-KI) and presenilin-1-M146 V knock-in (PS1-KI) mice. We also found that the "dopaminergic stabilizer" pridopidine (structurally similar to the S1R agonist R(+)-3-PPP), is a high-affinity S1R agonist and is synaptoprotective in a mouse model of Huntington disease. Here we tested whether pridopidine and R(+)-3-PPP are synaptoprotective in models of AD and whether this requires S1R. We also examined the effects of pridopidine on long-term potentiation (LTP), endoplasmic reticulum calcium and neuronal store-operated calcium entry (nSOC) in spines, all of which are dysregulated in AD, contributing to synaptic pathology. We report here that pridopidine and 3-PPP protect mushroom spines from Aβ oligomer toxicity in primary WT hippocampal cultures from mice. Pridopidine also reversed LTP defects in hippocampal slices resulting from application of Aβ oligomers. Pridopidine and 3-PPP rescued mushroom spines in hippocampal cultures from APP-KI and PS1-KI mice. S1R knockdown from lenti-viral shRNA expression destabilized WT mushroom spines and prevented the synaptoprotective effects of pridopidine in PS1-KI cultures. Knockout of PS1/2 destabilized mushroom spines and pridopidine was unable to prevent this. Pridopidine lowered endoplasmic reticulum calcium levels in WT, PS1-KO, PS1-KI and PS2 KO neurons, but not in PS1/2 KO neurons. S1R was required for pridopidine to enhance spine nSOC in PS1-KI neurons. Pridopidine was unable to rescue PS1-KI mushroom spines during pharmacological or genetic inhibition of nSOC. Oral pridopidine treatment rescued mushroom spines in vivo in aged PS1-KI-GFP mice. Pridopidine stabilizes mushroom spines in mouse models of AD and this requires S1R, endoplasmic reticulum calcium leakage through PS1/2 and nSOC. Thus, pridopidine may be useful to explore for the treatment of AD.
有证据表明，阿尔茨海默病（AD）中的认知能力下降是由于突触通讯（例如，蘑菇形“记忆刺”的丧失）和神经退行性过程的缺陷所致。这可能可以通过 sigma-1 受体（S1R）激动剂来治疗，S1R 激动剂具有广泛的神经保护作用，并调节突触可塑性。例如，我们之前发现混合毒蕈碱/S1R 激动剂 AF710B 可防止 APP 基因敲入（APP-KI）和早老素 1-M146V 基因敲入（PS1-KI）小鼠海马培养物中蘑菇刺的丢失。我们还发现，“多巴胺稳定剂”普里多宾（结构上与 S1R 激动剂 R(+)-3-PPP 相似）是一种高亲和力的 S1R 激动剂，可在亨廷顿病的小鼠模型中发挥突触保护作用。在这里，我们测试了普里多宾和 R(+)-3-PPP 是否在 AD 模型中具有突触保护作用，以及这是否需要 S1R。我们还研究了普里多宾对长时程增强（LTP）、内质网钙和神经元储存操纵的钙内流（nSOC）的影响，AD 中这些都失调了，导致了突触病理学。我们在这里报告说，普里多宾和 3-PPP 可保护原代 WT 海马培养物中的蘑菇刺免受 Aβ 寡聚物的毒性。普里多宾还逆转了 Aβ 寡聚物应用导致的海马切片中的 LTP 缺陷。普里多宾挽救了 APP-KI 和 PS1-KI 小鼠海马培养物中的蘑菇刺。来自 lentiviral shRNA 表达的 S1R 敲低使 WT 蘑菇刺不稳定，并阻止了普里多宾在 PS1-KI 培养物中的突触保护作用。PS1/2 的敲除使蘑菇刺不稳定，而普里多宾无法阻止这种情况。普里多宾降低了 WT、PS1-KO、PS1-KI 和 PS2 KO 神经元中的内质网钙水平，但不能降低 PS1/2 KO 神经元中的内质网钙水平。S1R 是普里多宾增强 PS1-KI 神经元中刺 nSOC 所必需的。普里多宾无法在 nSOC 的药理学或遗传抑制期间挽救 PS1-KI 蘑菇刺。口服普里多宾治疗可挽救体内年老的 PS1-KI-GFP 小鼠的蘑菇刺。普里多宾稳定 AD 小鼠模型中的蘑菇刺，这需要 S1R、PS1/2 通过内质网钙漏和 nSOC。因此，普里多宾可能对 AD 的治疗有用。
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