Chernyuk D, Callens M, Polozova M, Gordeev A, Chigriai M, Rakovskaya A, Ilina A, Pchitskaya E, Van den Haute C, Vervliet T, Bultynck G, Bezprozvanny I
Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnic University, Saint Petersburg, Russia.
KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
IBRO Neurosci Rep. 2023 Feb 23;14:273-283. doi: 10.1016/j.ibneur.2023.02.005. eCollection 2023 Jun.
Alzheimer's disease (AD) is the most common cause of dementia. An early feature of the AD pathology is the dysregulation of intracellular Ca signaling in neurons. In particular, increased Ca release from endoplasmic reticulum-located Ca channels, including inositol-1,4,5-trisphosphate type 1 receptors (IPR1) and ryanodine receptors type 2 (RyR2), have been extensively reported. Known for its anti-apoptotic properties, Bcl-2 also has the ability to bind to and inhibit the Ca-flux properties of IPRs and RyRs. In this study, the hypothesis that the expression of Bcl-2 proteins can normalize dysregulated Ca signaling in a mouse model of AD (5xFAD) and thereby prevent or slow the progression of AD was examined. Therefore, stereotactic injections of adeno-associated viral vectors expressing Bcl-2 proteins were performed in the CA1 region of the 5xFAD mouse hippocampus. In order to assess the importance of the association with IPR1, the Bcl-2 mutant was also included in these experiments. This K17D mutation has been previously shown to decrease the association of Bcl-2 with IPR1, thereby impairing its ability to inhibit IPR1 while not affecting Bcl-2's ability to inhibit RyRs. Here, we demonstrate that Bcl-2 protein expression leads to synaptoprotective and amyloid-protective effects in the 5xFAD animal model. Several of these neuroprotective features are also observed by Bcl-2 protein expression, suggesting that these effects are not associated with Bcl-2-mediated inhibition of IPR1. Potential mechanisms for this Bcl-2 synaptoprotective action may be related to its ability to inhibit RyR2 activity as Bcl-2 and Bcl-2 are equally potent in inhibiting RyR2-mediated Ca fluxes. This work indicates that Bcl-2-based strategies hold neuroprotective potential in AD models, though the underlying mechanisms requires further investigation.
阿尔茨海默病（AD）是痴呆最常见的病因。AD病理学的一个早期特征是神经元内细胞内钙信号传导失调。特别是，内质网定位的钙通道（包括1,4,5-三磷酸肌醇1型受体（IPR1）和2型兰尼碱受体（RyR2））的钙释放增加已被广泛报道。Bcl-2以其抗凋亡特性而闻名，它还能够结合并抑制IPR和RyR的钙通量特性。在本研究中，研究了Bcl-2蛋白的表达能否使AD小鼠模型（5xFAD）中失调的钙信号正常化，从而预防或减缓AD进展的假说。因此，在5xFAD小鼠海马体的CA1区域进行了立体定向注射表达Bcl-2蛋白的腺相关病毒载体。为了评估与IPR1结合的重要性，这些实验中还包括了Bcl-2突变体。先前已证明这种K17D突变会降低Bcl-2与IPR1的结合，从而损害其抑制IPR1的能力，同时不影响Bcl-2抑制RyR的能力。在此，我们证明Bcl-2蛋白表达在5xFAD动物模型中产生突触保护和淀粉样蛋白保护作用。Bcl-2蛋白表达也观察到了其中一些神经保护特征，这表明这些作用与Bcl-2介导的对IPR1的抑制无关。这种Bcl-2突触保护作用的潜在机制可能与其抑制RyR2活性的能力有关，因为Bcl-2和Bcl-2在抑制RyR2介导的钙通量方面同样有效。这项工作表明，基于Bcl-2的策略在AD模型中具有神经保护潜力，尽管其潜在机制需要进一步研究。
