Ettcheto Miren, Petrov Dmitry, Pedrós Ignacio, de Lemos Luisa, Pallàs Mercè, Alegret Marta, Laguna Juan Carlos, Folch Jaume, Camins Antoni
Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus, Tarragona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
Exp Gerontol. 2015 May;65:69-78. doi: 10.1016/j.exger.2015.03.010. Epub 2015 Mar 20.
Previous studies suggest that Alzheimer's disease (AD) neurobiology could not be explained solely by an increase in β-amyloid levels. Recently, it has been proposed that alterations in brain cholesterol metabolism may contribute to the pathogenesis of AD. In the present work, we focus on early changes in the hippocampal phenotypes of two mouse models in which cognitive impairments were previously described: a) the hypercholesterolemic LDL receptor knockout (LDLr -/-) and b) the APPswe/PS1dE9 (APP/PS1) transgenic model of familial AD. Our initial analysis, subsequent validation and additional experiments at the mRNA and protein levels demonstrate some parallels between the hippocampal phenotypes of these 2 mouse models, however our data suggest that the molecular mechanisms leading to cognitive decline are distinct in LDLr -/- and APP/PS1 animals. Genes related to cytokine signaling were significantly down-regulated in LDLr -/- mice when compared to both the wild-type and APP/PS1 mice, and these include prostaglandin-endoperoxide synthases 1 and 2 (ptgs1 and 2) and nerve grow factor (ngf). We have also detected reduced expression of genes related to lipid metabolism in LDLr -/- mice: peroxisome proliferator activated receptor gamma (pparg), pro-opiomelanocortin-alpha (pomc) and of protein kinase, AMP-activated, alpha 1 catalytic subunit of AMPK (prkaa1). Our array data also indicate that transcriptional activity of early genes involved in memory process, such as FBJ osteosarcoma oncogene (Fos) and the activity regulated cytoskeletal-associated protein (Arc) gene, are increased in the hippocampus of LDLr -/- mice. Several proteins like insulin degrading enzyme (IDE), PGC-1α, OXPHOS 1, NMDAR1 and cyclic AMP response element binding protein (CREB) are up-regulated in the LDLr -/- mice, while in the APP/PS1 mouse model only OXPHOS complexes 2, 3 and 5 are slightly downregulated. Further studies are necessary to understand the molecular pathways involved in memory loss in hypercholesterolemic LDLr -/- mice.
先前的研究表明，阿尔茨海默病（AD）的神经生物学不能仅用β-淀粉样蛋白水平的升高来解释。最近，有人提出脑胆固醇代谢的改变可能有助于AD的发病机制。在本研究中，我们关注两种先前已描述有认知障碍的小鼠模型海马表型的早期变化：a）高胆固醇血症低密度脂蛋白受体敲除（LDLr-/-）小鼠和b）家族性AD的APPswe/PS1dE9（APP/PS1）转基因模型。我们在mRNA和蛋白质水平的初步分析、后续验证及额外实验表明，这两种小鼠模型的海马表型存在一些相似之处，然而我们的数据表明，导致LDLr-/-小鼠和APP/PS1小鼠认知能力下降的分子机制是不同的。与野生型小鼠和APP/PS1小鼠相比，LDLr-/-小鼠中与细胞因子信号传导相关的基因显著下调，这些基因包括前列腺素内过氧化物合酶1和2（ptgs1和2）以及神经生长因子（ngf）。我们还检测到LDLr-/-小鼠中与脂质代谢相关的基因表达降低：过氧化物酶体增殖物激活受体γ（pparg）、促阿片黑素皮质激素α（pomc）以及AMP激活的蛋白激酶α1催化亚基（prkaa1）。我们的基因芯片数据还表明，参与记忆过程的早期基因，如FBJ骨肉瘤癌基因（Fos）和活性调节细胞骨架相关蛋白（Arc）基因，在LDLr-/-小鼠海马中的转录活性增加。几种蛋白质，如胰岛素降解酶（IDE）、PGC-1α、氧化磷酸化蛋白1、NMDAR1和环磷酸腺苷反应元件结合蛋白（CREB）在LDLr-/-小鼠中上调，而在APP/PS1小鼠模型中只有氧化磷酸化复合物2、3和5略有下调。有必要进行进一步研究以了解高胆固醇血症LDLr-/-小鼠记忆丧失所涉及的分子途径。
