Cholesterol-related genes in response to brain deafferentation in normal and transgenic mice
胆固醇相关基因对正常和转基因小鼠脑传入神经阻滞的反应
基本信息
- 批准号:RGPIN-2020-04702
- 负责人:
- 金额:$ 2.4万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2022
- 资助国家:加拿大
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Our team has documented over the years an elegant mechanism by which the injured adult brain uses the cholesterol and phospholipids released from dead/dying cells to feed surviving neurons with the lipids required for the proper rebuilding local synaptic networks. We call this process the cholesterol recycling cascade. Our team has already demonstrated that the intra- and extracellular transport of cholesterol by apolipoprotein E (apoE) and ABCA1, highly functional lipid transporters, is required and necessary for the replacement of synaptic networks in response to brain injury in rodents. In response, neuronal cell-surface receptors belonging to the LDL receptors family that recognize apoE-lipoprotein complexes mediate the internalization of the HDL-cholesterol used in the formation of new synapses. The complete absence of brain apoE or, of its main receptor, in knockout mice was shown to compromise i) synaptic integrity with aging, ii) lesion-induced synaptic recovery and iii) cognitive performance. We know very little about the triggering and regulating mechanisms controlling this cascade; i.e. the transport and packaging of cholesterol and phospholipids from the astroglial compartments toward the apoE-lipoprotein (HDL) assembly line, and the final LDL receptor (LDLR)-mediated internalisation. We know that certain ATP-Binding Cassette (ABC) proteins such as A1 are involved, facilitating the transfer of lipids to HDLs at the surface. Hypothesis: In response to neuronal loss, brain cholesterol is mobilized by astrocytes where the coordinated expression of ABCA1, A7 or G1 facilitates its movement toward the cell surface where apolipoprotein E awaits to catalyze the transfer of the lipids to extracellular apoE-rich HDL complexes. These lipid-enriched lipoproteins are subsequently used to feed neighboring neurons via the LDL receptors family which are tightly regulated by the presence of the so-called of SREBF2 and PCSK9 proteins; one is a potent activator of LDL receptor production (SREBF2) while the other (PCSK9) facilitate the LDLR elimination and catabolism. Subsequently, large amounts of lipids are engulfed by surviving neurons and are used to rebuild new dentritic and synaptic networks. Objectives: We propose to dissect the molecular cascade regulating the cholesterol recycling process by examining i) the intracellular transport of the lipids by the ABC transport system in glial cells in vivo during deafferentation and reinnervation, ii) the assembly of apoE-lipoprotein complexes in presence/absence of ABCA7 and LDLR in lesioned mice, iii) the interaction of apoE and ABCs with cell surface lipids and, iv) the binding and internalization of the apoE-HDL complex via the LDL receptors by neurons. Expected Outcome: We believe that these studies will provide crucial insights in regard to the molecular events leading to the activation of synaptic repair and the delivery of key lipid species during brain repair in the adult rodent brain.
多年来,我们的团队已经记录了一种优雅的机制,通过这种机制,受伤的成年大脑使用死亡/垂死细胞释放的胆固醇和磷脂来为幸存的神经元提供适当重建局部突触网络所需的脂质。我们称这个过程为胆固醇循环级联。我们的研究小组已经证明,高功能脂质转运蛋白载脂蛋白E(apoE)和ABCA 1对胆固醇的细胞内和细胞外转运是啮齿动物脑损伤后突触网络替代所必需的。作为响应,属于识别apoE-脂蛋白复合物的LDL受体家族的神经元细胞表面受体介导用于形成新突触的HDL-胆固醇的内化。在敲除小鼠中,脑apoE或其主要受体的完全缺失显示出损害i)随着衰老的突触完整性,ii)损伤诱导的突触恢复和iii)认知性能。 我们对控制这一级联反应的触发和调节机制知之甚少;即胆固醇和磷脂从星形胶质细胞隔室向apoE-脂蛋白(HDL)装配线的运输和包装,以及最终的LDL受体(LDLR)介导的内化。我们知道某些ATP结合盒(ABC)蛋白如A1参与其中,促进脂质在表面转移到HDL。假设:作为对神经元损失的响应,脑胆固醇被星形胶质细胞动员,在星形胶质细胞中ABCA 1,A7或G1促进其向细胞表面移动,在细胞表面载脂蛋白E等待催化脂质转移到细胞外apoE。丰富的HDL复合物。这些富含脂质的脂蛋白随后通过LDL受体家族用于喂养邻近的神经元,LDL受体家族受到所谓的SREBF 2和PCSK 9蛋白的存在的严格调节;一种是LDL受体产生的有效激活剂(SREBF 2),而另一种(PCSK 9)促进LDLR消除和catalysts。随后,大量的脂质被存活的神经元吞噬,并用于重建新的树突和突触网络。目的:我们建议通过检查i)在去传入和神经再支配期间,体内胶质细胞中ABC转运系统对脂质的细胞内转运,ii)在存在/不存在ABCA 7和LDLR的情况下,损伤小鼠中apoE-脂蛋白复合物的组装,iii)apoE和ABC与细胞表面脂质的相互作用,iv)apoE-HDL复合物通过LDL受体被神经元结合和内化。预期结果:我们相信,这些研究将提供至关重要的见解方面的分子事件,导致激活突触修复和关键脂质物种在成年啮齿动物大脑修复过程中的交付。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Poirier, Judes其他文献
Association of PPP2R1A with Alzheimer's disease and specific cognitive domains
- DOI:
10.1016/j.neurobiolaging.2019.06.008 - 发表时间:
2019-09-01 - 期刊:
- 影响因子:4.2
- 作者:
Miron, Justin;Picard, Cynthia;Poirier, Judes - 通讯作者:
Poirier, Judes
Differential regulation of ABCA1 and ABCG1 gene expressions in the remodeling mouse hippocampus after entorhinal cortex lesion and liver-X receptor agonist treatment
- DOI:
10.1016/j.brainres.2014.03.016 - 发表时间:
2014-05-08 - 期刊:
- 影响因子:2.9
- 作者:
Jasmin, Stephanie Belanger;Pearson, Vanessa;Poirier, Judes - 通讯作者:
Poirier, Judes
Association of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation
- DOI:
10.1016/j.jalz.2019.03.012 - 发表时间:
2019-07-01 - 期刊:
- 影响因子:14
- 作者:
Miron, Justin;Picare, Cynthia;Poirier, Judes - 通讯作者:
Poirier, Judes
Social isolation is linked to classical risk factors of Alzheimer's disease-related dementias.
- DOI:
10.1371/journal.pone.0280471 - 发表时间:
2023 - 期刊:
- 影响因子:3.7
- 作者:
Shafighi, Kimia;Villeneuve, Sylvia;Rosa Neto, Pedro;Badhwar, AmanPreet;Poirier, Judes;Sharma, Vaibhav;Medina, Yasser Iturria;Silveira, Patricia P.;Dube, Laurette;Glahn, David;Bzdok, Danilo - 通讯作者:
Bzdok, Danilo
Characteristics of subjective cognitive decline associated with amyloid positivity.
- DOI:
10.1002/alz.12512 - 发表时间:
2022-10 - 期刊:
- 影响因子:14
- 作者:
Janssen, Olin;Jansen, Willemijn J.;Vos, Stephanie J. B.;Boada, Merce;Parnetti, Lucilla;Gabryelewicz, Tomasz;Fladby, Tormod;Molinuevo, Jose Luis;Villeneuve, Sylvia;Hort, Jakub;Epelbaum, Stephane;Lleo, Alberto;Engelborghs, Sebastiaan;van der Flier, Wiesje M.;Landau, Susan;Popp, Julius;Wallin, Anders;Scheltens, Philip;Rikkert, Marcel Olde;Snyder, Peter J.;Rowe, Chris;Chetelat, Gael;Ruiz, Agustin;Marquie, Marta;Chipi, Elena;Wolfsgruber, Steffen;Heneka, Michael;Boecker, Henning;Peters, Oliver;Jarholm, Jonas;Rami, Lorena;Tort-Merino, Adria;Binette, Alexa Pichet;Poirier, Judes;Rosa-Neto, Pedro;Cerman, Jiri;Dubois, Bruno;Teichmann, Marc;Alcolea, Daniel;Fortea, Juan;Sanchez-Saudinos, M. Belen;Ebenau, Jarith;Pocnet, Cornelia;Eckerstrom, Marie;Thompson, Louisa;Villemagne, Victor;Buckley, Rachel;Burnham, Samantha;Delarue, Marion;Freund-Levi, Yvonne;Wallin, Asa K.;Ramakers, Inez;Tsolaki, Magda;Soininen, Hilkka;Hampel, Harald;Spiru, Luiza;Tijms, Betty;Ossenkoppele, Rik;Verhey, Frans R. J.;Jessen, Frank;Visser, Pieter Jelle - 通讯作者:
Visser, Pieter Jelle
Poirier, Judes的其他文献
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{{ truncateString('Poirier, Judes', 18)}}的其他基金
Cholesterol-related genes in response to brain deafferentation in normal and transgenic mice
胆固醇相关基因对正常和转基因小鼠脑传入神经阻滞的反应
- 批准号:
RGPIN-2020-04702 - 财政年份:2021
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Cholesterol-related genes in response to brain deafferentation in normal and transgenic mice
胆固醇相关基因对正常和转基因小鼠脑传入神经阻滞的反应
- 批准号:
RGPIN-2020-04702 - 财政年份:2020
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain
成年啮齿动物大脑修复和突触重塑过程中的细胞内和细胞外胆固醇转运系统
- 批准号:
RGPIN-2015-03790 - 财政年份:2019
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain
成年啮齿动物大脑修复和突触重塑过程中的细胞内和细胞外胆固醇转运系统
- 批准号:
RGPIN-2015-03790 - 财政年份:2018
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain
成年啮齿动物大脑修复和突触重塑过程中的细胞内和细胞外胆固醇转运系统
- 批准号:
RGPIN-2015-03790 - 财政年份:2017
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain
成年啮齿动物大脑修复和突触重塑过程中的细胞内和细胞外胆固醇转运系统
- 批准号:
RGPIN-2015-03790 - 财政年份:2016
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Intra- and extra-cellular cholesterol transport systems during brain repair and synaptic remodelling in the adult rodent brain
成年啮齿动物大脑修复和突触重塑过程中的细胞内和细胞外胆固醇转运系统
- 批准号:
RGPIN-2015-03790 - 财政年份:2015
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Role of apolipoproteins and ABC transporters during brain reinnervation in the adult mice
载脂蛋白和 ABC 转运蛋白在成年小鼠大脑神经支配中的作用
- 批准号:
355917-2009 - 财政年份:2013
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Role of apolipoproteins and ABC transporters during brain reinnervation in the adult mice
载脂蛋白和 ABC 转运蛋白在成年小鼠大脑神经支配中的作用
- 批准号:
355917-2009 - 财政年份:2012
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Role of apolipoproteins and ABC transporters during brain reinnervation in the adult mice
载脂蛋白和 ABC 转运蛋白在成年小鼠大脑神经支配中的作用
- 批准号:
355917-2009 - 财政年份:2011
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
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