BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides.
BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides.
复制标题
DOI：
10.1186/s13024-023-00611-w
复制
发表时间：
2023-05-04
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
作者：
淀粉样β肽（Aβ）在脑中的异常积累诱导阿尔茨海默病（AD）的一系列病理变化，因此正在探索抑制Aβ生成所需的BACE 1以通过减少Aβ积累来治疗AD。由于Bace 1基因敲除小鼠表现出反应性星形胶质细胞数量增加，AD大脑具有围绕淀粉样斑块的反应性星形胶质细胞，我们研究了BACE 1在星形胶质细胞中的作用，并确定BACE 1是否调节星形胶质细胞功能。我们使用来自Bace 1 KO小鼠和野生型对照同窝仔的纯化星形胶质细胞进行了无偏倚的单细胞RNA-seq（scRNA-seq）。还使用在成年阶段具有Bace 1条件性缺失的AD小鼠进行了类似的scRNA-seq（5xFAD; Bace 1fl/fl;UBC-creER与5xFAD; Bace 1fl/fl对照相比）。我们比较了星形胶质细胞和反应性星形胶质细胞簇的转录组，并确定了几个差异表达的基因，这是进一步验证使用Bace 1 KO星形胶质细胞培养。使用在5xFAD背景中具有星形胶质细胞特异性Bace 1敲除的小鼠来比较淀粉样蛋白沉积。使用培养的星形胶质细胞的机制研究被用来识别BACE 1底物的基因表达和信号传导活性的变化。 在改变的基因中，Cxcl 14和Clu显著上调，并通过测量蛋白质水平进行验证。此外，BACE 1缺陷增强星形胶质细胞Aβ的摄取和降解，并且这种作用被Clu的siRNA敲低显著减弱。机制研究表明，BACE 1缺乏废除星形胶质细胞胰岛素受体（IR）的切割，这可能会增强Clu和Cxcl 14的表达。从星形胶质细胞特异性敲除Bace 1小鼠（Bace 1 fl/fl;Gfap-cre）中急性分离的星形胶质细胞显示出CLU和IR的相似增加。此外，在5xFAD背景下，星形胶质细胞特异性敲除Bace 1通过增强清除率导致皮质Aβ斑块负荷显著减弱。总之，我们的研究表明，星形胶质细胞中的BACE 1可能通过控制胰岛素受体途径调节Clu和Cxcl 14的表达，抑制星形胶质细胞BACE 1是增强Aβ清除的潜在替代策略。在线版本包含补充材料，可通过10.1186/s13024-023-00611-w获得。
Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer’s disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions. We conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates. Similar scRNA-seq was also conducted using AD mice with conditional deletion of Bace1 in the adult stage (5xFAD;Bace1fl/fl;UBC-creER compared to 5xFAD;Bace1fl/fl controls). We compared the transcriptomes of astrocyte and reactive astrocyte clusters and identified several differentially expressed genes, which were further validated using Bace1 KO astrocyte cultures. Mice with astrocyte-specific Bace1 knockout in 5xFAD background were used to compare amyloid deposition. Mechanistic studies using cultured astrocytes were used to identify BACE1 substrates for changes in gene expression and signaling activity. Among altered genes, Clusterin (Clu) and Cxcl14 were significantly upregulated and validated by measuring protein levels. Moreover, BACE1 deficiency enhanced both astrocytic Aβ uptake and degradation, and this effect was significantly attenuated by siRNA knockdown of Clu. Mechanistic study suggests that BACE1 deficiency abolishes cleavage of astrocytic insulin receptors (IR), and this may enhance expression of Clu and Cxcl14. Acutely isolated astrocytes from astrocyte-specific knockout of Bace1 mice (Bace1 fl/fl;Gfap-cre) show similar increases in CLU and IR. Furthermore, astrocyte-specific knockout of Bace1 in a 5xFAD background resulted in a significant attenuation in cortical Aβ plaque load through enhanced clearance. Together, our study suggests that BACE1 in astrocytes regulates expression of Clu and Cxcl14, likely via the control of insulin receptor pathway, and inhibition of astrocytic BACE1 is a potential alternative strategy for enhancing Aβ clearance. The online version contains supplementary material available at 10.1186/s13024-023-00611-w.
登录
查看更多内容
DOI：
10.1016/j.jalz.2017.11.006
发表时间：
2018-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Chung J;Wang X;Maruyama T;Ma Y;Zhang X;Mez J;Sherva R;Takeyama H;Alzheimer's Disease Neuroimaging Initiative;Lunetta KL;Farrer LA;Jun GR
通讯作者：
Jun GR
影响因子：
15.1
作者：
Bettens K;Vermeulen S;Van Cauwenberghe C;Heeman B;Asselbergh B;Robberecht C;Engelborghs S;Vandenbulcke M;Vandenberghe R;De Deyn PP;Cruts M;Van Broeckhoven C;Sleegers K
通讯作者：
Sleegers K
影响因子：
5.3
作者：
Chacón-Quintero MV;Pineda-López LG;Villegas-Lanau CA;Posada-Duque R;Cardona-Gómez GP
通讯作者：
Cardona-Gómez GP
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
5.3
作者：
Hoe, Hyang-Sook;Cooper, Matthew J.;Rebeck, G. William
通讯作者：
Rebeck, G. William