Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, H3A 2B4, Montréal, QC, Canada.
Department of Biochemistry, Microbiology, Immunology University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
Cell Death Dis. 2022 Apr 9;13(4):325. doi: 10.1038/s41419-022-04784-y.
We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.
我们之前曾表明，辛伐他汀（SV）可在阿尔茨海默病（AD）小鼠模型中恢复记忆，同时使海马 CA1 神经元中与记忆相关的即刻早期基因的蛋白水平正常化。在这里，我们研究了海马记忆途径中的年龄相关变化，以及 SV 的有益作用是否与 Wnt/β-catenin 途径中的增强神经发生和信号有关。APP 小鼠和野生型（WT）同窝对照小鼠在 3 个月龄时，齿状回中的增殖（Ki67 阳性核）和未成熟（双皮质素（DCX）阳性）颗粒细胞数量相当。在 4 个月时，Ki67 或 DCX 阳性细胞急剧减少，并一直保持在较少的数量，直到 APP 小鼠的终点（6 个月）。在 6 月龄的 APP 小鼠中，DCX 未成熟神经元分子层中的树突延伸较短，SV 完全使该缺陷正常化。同样，尽管 APP 小鼠中成熟的颗粒细胞（钙结合蛋白免疫阳性）减少，且 SV 未使其恢复，但 SV 处理使它们的树突分支正常化至对照水平。SV 增加了 Prox1 蛋白水平（↑67.7%，p<0.01），这是 Wnt/β-catenin 信号的靶标，而显著降低（↓61.2%，p<0.05）了 APP 小鼠中上调的β-catenin 依赖性 Wnt 途径抑制剂 DKK1 的水平。在 APP 小鼠中，SV 的益处可通过 Wnt/β-catenin 特异性激动剂 WAY-262611 来重现，而当在 SV 治疗的最后一个月接受 Wnt/β-catenin 途径抑制剂 XAV939 时，它们完全被消除。我们的结果表明，通过下调 DKK1 激活 Wnt-β-catenin 途径是 SV 神经元和认知益处的基础。
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