Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

作者全名:"Xiong, Monica; Wang, Chao; Gratuze, Maud; Saadi, Fareeha; Bao, Xin; Bosch, Megan E.; Lee, Choonghee; Jiang, Hong; Serrano, Javier Remolina; Gonzales, Ernesto R.; Kipnis, Michal; Holtzman, David M."

作者地址:"[Xiong, Monica; Gratuze, Maud; Saadi, Fareeha; Bao, Xin; Bosch, Megan E.; Lee, Choonghee; Jiang, Hong; Serrano, Javier Remolina; Gonzales, Ernesto R.; Kipnis, Michal; Holtzman, David M.] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, Dept Neurol,Hope Ctr Neurol Disorders, St Louis, MO 63110 USA; [Xiong, Monica] Washington Univ, Sch Med, Div Biol & Biomed Sci DBBS, St Louis, MO 63110 USA; [Xiong, Monica] Genentech Inc, 1 DNA Way, South San Francisco, CA 94080 USA; [Wang, Chao] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China; [Gratuze, Maud] Aix Marseille Univ, Inst Neurophysiopathol INP, CNRS, UMR7051, F-13005 Marseille, France"

通信作者:"Holtzman, DM (通讯作者),Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, Dept Neurol,Hope Ctr Neurol Disorders, St Louis, MO 63110 USA."

来源:MOLECULAR NEURODEGENERATION

ESI学科分类:NEUROSCIENCE & BEHAVIOR

WOS号:WOS:000953023000001

JCR分区:Q1

影响因子:14.9

年份:2023

卷号:18

期号:1

开始页: 

结束页: 

文献类型:Article

关键词:APOE; Cerebral amyloid angiopathy; Cerebrovasculature; Astrocyte; Amyloid-beta

摘要:"Background Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-beta (A beta) accumulation in the brain, although A beta deposits mostly in the brain parenchyma in AD and in the cerebrovas-culature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the epsilon 4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.Methods We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for A beta plaque and CAA pathology, gliosis, and vascular integrity.Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar A beta from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall A beta-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.Conclusion In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar A beta deposition in the vasculature, is sufficient to reduce A beta-mediated gliosis and cerebrovascular dysfunction."

基金机构:"NIH [AG062027, RF1NS090934, RF1AG047644, R01 NS034467, P01 AG078106]; BrightFocus foundation [A2018128F, A2020257F]; Cure Alzheimer's Fund; JPB Foundation"

基金资助正文:"This work was supported by NIH grants AG062027 (M.X.), RF1NS090934 (D.M.H.), RF1AG047644 (D.M.H.), R01 NS034467 (D.M.H.), P01 AG078106 (D.M.H.), the BrightFocus foundation A2018128F (C.W.) and A2020257F (M.G.), Cure Alzheimer's Fund (D.M.H.), and the JPB Foundation (D.M.H.). Images scanned on the Hamamatsu NanoZoomer digital pathology system is courtesy of the Hope Center Alafi Neuroimaging Laboratory."