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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Research advances on role of CD2AP in pathogenesis of Alzheimer's disease

  • ZHANG Lingliang ,
  • LUO Hong ,
  • ZHANG Xian ,
  • CAN Dan ,
  • ZHANG Yunwu
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  • Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen 361102

Received date: 2020-04-07

  Revised date: 2020-04-08

  Online published: 2020-06-25

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and has two major pathological hallmarks as senile plaques and neurofibrillary tangles that are composed of β-amyloid (Aβ) peptides and hyperphosphorylated microtubule associated protein Tau, respectively. CD2AP (CD2-associated protein) is an adaptor protein and involved in intracellular protein trafficking and cytoskeletion reorganization. Recently CD2AP has been identified as a risk factor of AD. Current evidence suggests that CD2AP may affect Aβ production and deposition and mediate Tau neurotoxicity. Moreover, CD2AP may modulate the integrity of the blood-brain barrier and the transport of synaptic vesicles. Further study on the role of CD2AP in AD may strengthen our understanding on the molecular mechanism underlying the pathogenesis of AD.

Cite this article

ZHANG Lingliang , LUO Hong , ZHANG Xian , CAN Dan , ZHANG Yunwu . Research advances on role of CD2AP in pathogenesis of Alzheimer's disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2020 , 3(2) : 141 -146 . DOI: 10.3969/j.issn.2096-5516.2020.02.010

阿尔茨海默病(Alzheimer's disease, AD)是一种以损伤记忆、行为和自主能力为特征的进行性神经变性疾病。在死后的AD患者脑组织中发现AD的主要病理学特征为神经元细胞外的神经炎症斑块以及胞内的神经原纤维缠结。其中神经炎症斑块的主要组成成分为错误折叠和聚集的β-淀粉样肽(β-amyloid, Aβ),而神经原纤维缠结的主要组成成分为过度磷酸化的微管结合蛋白Tau[1]。根据发病年龄,AD可分为早发性AD(early-onset Alzheimer's disease, EOAD)和晚发性AD(late-onset Alzheimer's disease, LOAD)两类。EOAD主要由家族性遗传致病基因突变导致,目前公认发生在编码淀粉样肽前体蛋白(amyloid-β precursor protein, APP)、早老素1(presenilin-1, PS1)和早老素2(presenilin-2, PS2)这三个蛋白的基因上的突变会导致EOAD[2-3]。LOAD的发病由多种因素导致,包括基因突变以及环境因素。于1993年被证实的载脂蛋白E(apolipoprotein E)编码基因APOE的ε4等位基因一直被认为是LOAD的主要致病基因[4]。然而,APOE ε4基因并不是存在于所有的LOAD的病例中。在近几年的全基因组关联研究(genome wide association studies, GWAS)分析中发现了许多其他的和LOAD相关的基因,其中包括编码CD2相关蛋白(CD2-associated protein, CD2AP)的基因CD2AP,也称作Casligand with multiple SH3 domains(CMS)[5-6]。在随后的研究中发现CD2AP与Aβ的生成和沉积、Tau蛋白介导的神经毒性以及突触囊泡转运有关。因此,本文就目前CD2AP在AD中的研究进展做一简要综述。

1 CD2AP简介

人源CD2AP基因位于6号染色体上,具有18个外显子,编码的CD2AP蛋白具有639个氨基酸,分子量在71 kD左右。小鼠Cd2ap基因位于17号染色体上,同样具有18个外显子,编码的小鼠CD2AP蛋白有637个氨基酸。CD2AP蛋白是一种支架蛋白,最初因为它和T细胞中的跨膜蛋白CD2有相互作用,促进CD2聚集并稳定T细胞和抗原提呈细胞的连接,于1998年被发现并命名[7]。CD2AP主要由靠近N末端的三个连续的SH3结构域、中间的富含脯氨酸区域和C末端的一个卷曲结构域构成(如图1)。这些结构域中包含许多肌动蛋白结合位点以及膜蛋白结合位点,通过与肌动蛋白以及膜蛋白的相互作用调节细胞骨架并且参与到受体内吞和囊泡转运过程[8]。CD2AP在全身各个部位均有不同程度的表达,其中在胃、十二指肠、结肠、肾脏等部位有着相对较高水平的表达,而在肾脏足细胞中表达量最高[9]。在肾脏足细胞中,CD2AP定位于足细胞的细胞骨架和相邻两个足细胞之间的特殊连接点狭缝膈膜(slit diaphragm, SD)处。CD2AP在狭缝膈膜处与肾病蛋白(nephrin)以及狭缝膈膜蛋白(podocin)等相互作用,共同维持足细胞与SD在肾小球滤过过程中发挥的重要作用[9-11]。CD2AP是维持肾小球功能正常的必需蛋白,纯合的Cd2ap基因敲除小鼠因足细胞足突完整性丧失而发生进行性肾小球功能障碍,出生6~7周内死于肾衰竭[12]。此外,虽然CD2AP在大脑中的表达量较少[9],但是在艾伦脑图谱(Allen brain atlas)中的原位杂交实验清楚地显示了鼠脑皮层和海马神经元中存在Cd2ap mRNA表达,值得注意的是Cd2ap在一些具有高度可塑性的鼠脑区域有着相对较高的表达,如皮层、海马和小脑等。另外,Cd2ap在小鼠体外培养的原代神经元的树突内体中被检出有着相对较高的表达量[13]。并且神经元与足细胞相似之处在于两者都具有丰富的肌动蛋白突起,并共享肌动蛋白调节剂,如突触足蛋白和大脑发育调节蛋白等[14]。因此,CD2AP在中枢神经系统中也可能发挥着重要功能。
图1 CD2AP基因和蛋白结构示意图

2 CD2AP与AD

2.1 CD2AP是AD的风险因子

2011年,研究人员在对AD的GWAS分析中首次发现CD2AP基因突变与AD的发生发展相关[5-6]。后来的研究在针对来自东亚、美国、加拿大和欧洲人群进行荟萃分析同样发现CD2AP基因的单核苷酸多态性位点(single nucleotide polymorphism, SNP)rs9349407与AD之间具有明显的相关性[15]。Shulman等通过研究725名有完整神经病理学评估的死者,同样发现rs9349407位点与神经元斑块病理有关[16]。Vardarajan等报道了CD2AP的错义突变(K633R)在白种人中与LOAD密切相关[17]。Tao等发现中国南方汉族人群中CD2AP位点rs9296559与散发性AD有关,并且散发性AD患者外周血淋巴细胞中CD2AP基因的表达明显低于对照组[18]。而位点rs9473117在中国南方人口中与EOAD密切相关[19]。此外,在通过对中国AD患者进行全基因组测序(whole-genome sequencing, WGS)研究中发现,CD2AP的另一位点rs10948363作为少数几个在GWAS中有重复的位点之一,也与AD的发生有很大关联[20]。这些研究分析表明,CD2AP基因的异常突变与AD发生的风险性密切相关。因此,对于CD2AP基因上与AD相关的SNP的检测,或许可以成为AD的预防和诊断的辅助手段。

2.2 CD2AP影响APP的蛋白转运和Aβ的生成

近年来,许多研究发现AD与膜转运过程异常密切相关。目前已知APP在胞内的水解途径有两种:淀粉样蛋白水解途径(β途径)以及非淀粉样蛋白水解途径(α途径)。Aβ是由APP在β-分泌酶1(BACE1)和γ-分泌酶(γ-secretase)作用下经过淀粉样蛋白途径水解产生。APP通过淀粉样蛋白途径水解是由APP的亚细胞定位以及其在细胞膜、内体和溶酶体转运过程中与BACE1和γ-分泌酶的接触情况决定的[21-23]。首先,APP在BACE1的水解作用下产生可溶性胞外段APP(soluble ectodomain region of APP, sAPPβ)和C-末端片段(C-terminal fragment, CTFβ),然后CTFβ又在γ-分泌酶的水解作用下产生40或42个氨基酸长度的Aβ片段,即Aβ40和Aβ42[24]
CD2AP作为一个与肌动蛋白有关的适配器蛋白,与Rab家族的许多成员一起参与运输小泡到靶膜的停靠过程,也参与到内体形态的调节中去[8]。CD2AP还参与表皮生长因子受体的内吞和转运过程[25-26]。更为重要的是,CD2AP与神经元中的Rab5有着很好的共定位,这无疑将CD2AP与神经细胞中内体的转运联系起来[13,27]。一些研究也发现CD2AP参与到APP在细胞内转运切割产生Aβ的过程中。Furusawa等研究表明在细胞水平过表达CD2AP会加速APP从早期内体到晚期内体的转运,从而加快APP降解的起始过程,但却并不影响APP降解速率,而且过表达CD2AP会促进饥饿诱导引发的APP在晚期内体中聚集并被溶酶体降解的过程[28]。此外,Ubelmann等研究显示CD2AP会影响APP在神经元中早期内体表面的滞留时间,抑制CD2AP的表达会使得APP与BACE1在神经元早期内体中相遇概率增加,影响APP的切割产生Aβ的过程,继而影响斑块的产生[13]。但是Liao等研究报道在过表达APP的N2a-APP695细胞系中敲低CD2AP会使得膜上APP以及Aβ的释放减少,Aβ42/Aβ40下降,而且在1月龄敲除Cd2ap的APP/PS1小鼠中,Aβ42/Aβ40也同样呈现下降趋势[29]。因此,虽然CD2AP能够影响APP的转运和Aβ的产生,但是这一作用在AD疾病过程中的参与还有待更深入地研究。

2.3 CD2AP缺失加强Tau蛋白介导的神经毒性

CD2AP对AD的另一病理特征,即由Tau蛋白介导的神经毒性也有一定影响。研究发现,CD2AP的SNP位点rs9349407与脑脊液中的Tau蛋白总量的增加有关[30]。在AD模型的果蝇中,研究人员发现cindr是人源CD2AP的同源基因,通过RNA干扰敲低成年果蝇中的cindr基因后,敲低cindr的成年果蝇存活时间明显缩短,Tau蛋白对神经元的毒性上升,神经元缺失增加[31]。在泛神经元中表达人源Tau蛋白的成年果蝇模型中,cindr缺失加快了年龄依赖性凋亡神经元的变性,而这种作用与cindr突变体会损害泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS)继而影响蛋白的周转有关[32]。此外,CD2AP通过结合转运所需内体分选复合体(endosomal sorting complex required for transport, ESCRT)的一个组分ALG-2结合蛋白(ALG-2-interacting protein X, ALIX),参与到外泌体的形成和装填过程中[25]。在HEK293细胞中,敲除CD2AP会导致一个外泌体货运蛋白(exosomal cargo protein)GPRC5B在细胞表面而不是在核周围聚集,提示CD2AP可能参与到外泌体释放到胞外的过程[33]。CD2AP在外泌体的形成、装填和释放过程中的参与或许也影响了Tau病理途径的传播过程,但具体参与过程仍有待进一步证实。这些研究分析表明,CD2AP在Tau蛋白介导的病理过程中发挥着重要作用。

2.4 CD2AP参与调节突触及囊泡释放

神经突触是神经元之间信号传递的核心结构,突触功能的异常与认知功能的损伤有着密不可分的联系。在AD的早期阶段就出现突触功能的紊乱,但此时突触的数量没有明显的变化。而在AD的中后期出现了大量的突触丢失和神经元死亡,患者认知能力也随之大幅下降[34-36]。Ojelade等[32]最近研究显示,cindr作为人源CD2AP在果蝇中的同源基因,参与到突触的成熟过程,cindr的突变体破坏突触囊泡的循环和释放,损害了突触可塑性。Cindr还与14-3-3ζ相互作用,调节UPS,影响突触素和质膜钙ATP酶(plasma membrane Ca2+-ATPase, PMCA)的转换。cindr的缺失使PMCA水平升高,并降低胞质钙水平。并且在小鼠中发现CD2AP与突触蛋白的稳定性有关,而在人类死后大脑中CD2AP蛋白水平与突触蛋白丰度呈负相关。CD2AP还可以调节神经元轴突的长度与复杂性以及生长锥丝状伪足的数量,通过协调神经生长因子(nerve growth factor, NGF)信号调节完整成年轴突侧枝发芽和结构可塑性[27]

2.5 CD2AP影响血脑屏障的完整性

神经影像学研究已经证明,早期AD患者和其他神经变性疾病的血脑屏障功能被破坏,在观察死后AD患者脑组织也得到了相同结论。血脑屏障的破坏会导致神经毒性血源性碎片、细胞以及微生物病原体流入大脑并且引起炎症反应以及相关免疫应答,这可以启动多种途径引起AD等神经变性疾病[37]。脑血管内皮细胞是构成血脑屏障的重要组成部分,而CD2AP在脑血管内皮细胞中有着很高的表达[38]。Rasmussen等开展的荟萃分析显示CD2AP的SNP位点rs10948363与血管性痴呆密切相关[39],而且在Yao等[40]CD2AP的异常突变和脑血流量相关性的互补分析中显示CD2AP基因的异常突变与大脑左角区域(left angular region, L-AG)脑血流量变化显著相关。Cd2ap纯合敲除小鼠除了表现出轻度的运动障碍和焦虑障碍外,血脑屏障的完整性也遭到一定程度的破坏[39]。此外,越来越多的证据表明,很多AD患者伴随癫痫症状的发生[41],癫痫的发生与血脑屏障的功能障碍密切相关[42],而Cd2ap纯合敲除小鼠对戊四唑(pentylenetetrazol, PTZ)诱发癫痫发作的潜伏期明显缩短,并且因癫痫发作的小鼠死亡率提高[38]。这些研究结果表明CD2AP异常表达从而导致血脑屏障异常很可能是其增加AD风险性的一个重要原因。

3 结语

CD2AP参与调节早期内体的形态以及早期内体向溶酶体的转移过程,并与细胞内蛋白转运和降解、囊泡转运以及细胞骨架的重塑密切相关。CD2AP作为AD的风险因子,其异常可能从多个层面参与疾病,包括:影响APP的转运及降解过程,从而影响Aβ的生成和沉积;参与Tau蛋白介导的神经毒性;干扰神经突触功能和囊泡释放;破坏血脑屏障的完整性(如图2)。然而,CD2AP参与AD的发生发展过程的确切分子机制尚不十分清楚。进一步深入探索CD2AP的生理和病理功能,将为AD的致病机制和防治提供新的思路。
图2 CD2AP异常参与AD的相关通路
[1]
Scheltens, P, Blennow, K, Breteler, MM, et al. Alzheimer's disease[J]. Lancet, 2016, 388(10043): 505-517.

DOI PMID

[2]
Lanoiselee, HM, Nicolas, G, Wallon, D, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases[J]. PLoS Med, 2017, 14(3): e1002270.

DOI

[3]
Kennedy, JL, Farrer, LA, Andreasen, NC, et al. The genetics of adult-onset neuropsychiatric disease: complexities and conundra?[J]. Science, 2003, 302(5646): 822-826.

PMID

[4]
Laws, SM, Hone, E, Gandy, S, et al. Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription[J]. J Neurochem, 2003, 84(6): 1215-1236.

DOI

[5]
Naj, AC, Jun, G, Beecham, GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease[J]. Nat Genet, 2011, 43(5): 436-441.

DOI

[6]
Hollingworth, P, Harold, D, Sims, R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease[J]. Nat Genet, 2011, 43(5): 429-435.

DOI PMID

[7]
Dustin, ML, Olszowy, MW, Holdorf, AD, et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts[J]. Cell, 1998, 94(5): 667-677.

PMID

[8]
Cormont, M, Meton, I, Mari, M, et al. CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl[J]. Traffic, 2003, 4(2): 97-112.

DOI

[9]
Li, C, Ruotsalainen, V, Tryggvason, K, et al. CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere[J]. Am J Physiol Renal Physiol, 2000, 279(4): F785-F792.

[10]
Shih, NY, Li, J, Cotran, R, et al. CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain[J]. Am J Pathol, 2001, 159(6): 2303-2308.

PMID

[11]
Schwarz, K, Simons, MS, Reiser, J, et al. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin[J]. J Clin Invest, 2001, 108(11): 1621-1629.

PMID

[12]
Shih, NY, Li, J, Karpitskii, V, et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein[J]. Science, 1999, 286(5438): 312-315.

PMID

[13]
Ubelmann, F, Burrinha, T, Salavessa, L, et al. Bin1 and CD2AP polarise the endocytic generation of beta-amy- loid[J]. EMBO Rep, 2017, 18(1):102-122.

DOI PMID

[14]
Peitsch, WK, Hofmann, I, Endlich, N, et al. Cell biological and biochemical characterization of drebrin complexes in mesangial cells and podocytes of renal glomeruli[J]. J Am Soc Nephrol, 2003, 14(6):1452-1463.

PMID

[15]
Chen, HY, Wu, GH, Jiang, YS, et al. Analyzing 54, 936 samples supports the association between CD2AP rs9349407 polymorphism and Alzheimer's disease susceptibility[J]. Mol Neurobiol, 2015, 52(1): 1-7.

DOI

[16]
Shulman, JM, Chen, KW, Keenan, BT, et al. Genetic susceptibility for Alzheimer disease neuritic plaque pathology[J]. JAMA Neurol, 2013, 70(9):1150-1157.

DOI PMID

[17]
Vardarajan, BN, Ghani, M, Kahn, A, et al. Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci[J]. Ann of Neurol, 2015, 78(3): 487-498.

DOI

[18]
Tao, QQ, Liu, ZJ, Sun, YM, et al. Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer's disease[J]. Neurobiol Aging, 2017, 56: 212. e5-212. e10.

[19]
Yan, Y, Zhao, A, Qui, Y, et al. Genetic association of FERMT2, HLA-DRB1, CD2AP, and PTK2B polymorphisms with Alzheimer's disease risk in the southern Chinese population[J]. Front Aging Neurosci, 2020, 12: 16.

DOI PMID

[20]
Zhou, XP, Chen, Y, Mok, KY, et al. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis[J]. Proc Natl Acad Sci U S A, 2018, 115(8): 1697-1706.

DOI

[21]
Nalivaeva, NN, Turner, AJ, The amyloid precursor protein: a biochemical enigma in brain development, function and disease[J]. FEBS Lett, 2013, 587(13): 2046-2054.

DOI PMID

[22]
Selkoe, DJ, Alzheimer's disease: genes, proteins, and therapy[J]. Physiol Rev, 2001, 81(2): 741-766.

PMID

[23]
Ubhi, K, Masliah, E, Alzheimer's disease: recent advances and future perspectives[J]. Alzheimers Dis, 2013, 33 (Suppl 1): S185-S194.

[24]
Bursavich, MG, Harrison, BA, Blain, JF, et al. Gamma secretase modulators: new Alzheimer's drugs on the horizon?[J]. J Med Chem, 2016, 59(16): 7389-7409.

DOI PMID

[25]
Rouka, E, Simister, PC, Janning, M, et al. Differential recognition preferences of the three Src homology 3 (SH3) domains from the adaptor CD2-associated protein (CD2AP) and direct association with Ras and Rab interactor 3 (RIN3)[J]. J Biol Chem, 2015, 290(42): 25275-25292.

DOI

[26]
Lynch, DK, Winata, SC, Lyons, RJ, et al. A cortactin- CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton[J]. J Biol Chem, 2003, 278(24): 21805-21813.

DOI

[27]
Harrison, BJ, Venkat, G, Lamb, JL, et al. The adaptor protein CD2AP is a coordinator of neurotrophin signaling-mediated axon arbor plasticity[J]. J Neurosci, 2016, 36(15): 4259-4275.

DOI

[28]
Furusawa, K, Takasugi, T, Chiu, YW, et al. CD2- associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway[J]. J Biol Chem, 2019, 294(28): 10886-10899.

DOI PMID

[29]
Liao, F, Jiang, H, Srivatsan, S, et al. Effects of CD2-associated protein deficiency on amyloid-beta in neuroblastoma cells and in an APP transgenic mouse model[J]. Mol Neurodegener, 2015, 10: 12.

DOI PMID

[30]
de Matos, MR, Ferreira, C, Herukka, SK, et al. Quantitative genetics validates previous genetic variants and identifies novel genetic players influencing Alzheimer's disease cerebrospinal fluid biomarkers[J]. J Alzheimers Dis, 2018, 66(2): 639-652.

DOI

[31]
Shulman, JM, Imboywa, S, Giagtzoglou, N, et al. Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms[J]. Hum Mol Genet, 2014, 23(4): 870-877.

DOI PMID

[32]
Ojelade, SA, Lee, TV, Giagtzoglou, N, et al. cindr, the drosophila homolog of the CD2AP Alzheimer's disease risk gene, is required for synaptic transmission and proteostasis[J]. Cell Rep, 2019, 28(7): 1799-1813. e5.

DOI

[33]
Kwon, SH, Oh, S, Nacke, M, et al. Adaptor protein CD2AP and L-type lectin LMAN2 regulate exosome cargo protein trafficking through the Golgi complex[J]. J Biol Chem, 2017, 292(40): 16523.

DOI

[34]
Yao, PJ, Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer's disease[J]. Trends Neurosci, 2004, 27(1): 24-29.

DOI

[35]
Terry, RD, Masliah, E, Salmon, DP, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment[J]. Ann Neurol, 1991, 30(4): 572-580.

PMID

[36]
DeKosky, ST, Scheff, SW, Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity[J]. Ann Neurol, 1990, 27(5): 457-464.

PMID

[37]
Sweeney, MD, Sagare, AP, Zlokovic, BV, et al. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders[J]. Nat Rev Neurol, 2018, 14(3): 133-150.

[38]
Cochran, JN, Rush, T, Buckingham, SC, et al. The Alzheimer's disease risk factor CD2AP maintains blood- brain barrier integrity[J]. Hum Mol Genet, 2015, 24(23): 6667-6674.

DOI

[39]
Rasmussen, IJ, Tybjaerg-Hansen, A, Rasmussen, KL, et al. Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74, 754 individuals[J]. Eur J Epidemiol, 2019, 34(6): 579-590.

DOI PMID

[40]
Yao, XH, Risacher, SL, Nho, K, et al. Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene[J]. Neurobiol Aging, 2019, 81: 213-221.

DOI

[41]
Vossel, KA, Tartaglia, MC, Nygaard, HB, et al. Epileptic activity in Alzheimer's disease: causes and clinical relevance[J]. Lancet Neurol, 2017, 16(4): 311-322.

DOI PMID

[42]
Bankstahl, M, Breuer, H, Leiter, I, et al. Blood-brain barrier leakage during early epileptogenesis is associated with rapid remodeling of the neurovascular unit[J]. eNeuro, 2018, 5(3): ENEURO. 0123-18. 2018.

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