引用本文
郑斌, 李金娜. 弓形虫感染与阿尔茨海默病相关性的研究进展[J]. 中国人兽共患病学报, 2018,34(10): 931-935
ZHENG Bin, LI Jin-na. Advances on the association between Toxoplasma gondii infection and Alzheimer̓s disease [J]. Chinese Journal of Zoonoses, 2018,34(10): 931-935.  
Doi: 10.3969/j.issn.1002-2694.2018.00.162
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Copyright©2018, 中国人兽共患病学报
中国人兽共患病学报
弓形虫感染与阿尔茨海默病相关性的研究进展
郑斌, 李金娜
新乡医学院寄生虫学教研室,新乡 453003
收稿日期: 2018-05-02
资助项目: 河南省科技厅科技攻关项目(No.172102310404); 新乡市科技局科技攻关项目(No.GXGG16017); 新乡医学院博士科研启动基金项目(No. 100777)
摘要

阿尔茨海默病(Alzheimer̓s disease, AD)是老年人常见的一种中枢神经系统退行性疾病,AD的发病机制尚未完全阐明。多项研究发现:AD患者血清弓形虫抗体阳性率高于对照组;弓形虫感染可诱发或加重认知障碍、记忆进行性减退等AD样症状;弓形虫感染引起脑组织Aβ沉积、Tau蛋白高度磷酸化和神经元损伤等AD样病变。研究结果提示弓形虫感染与AD具有关联性。本文就弓形虫感染与AD相关性的研究进展做一综述。

关键词: 刚地弓形虫; 阿尔茨海默病; β-淀粉样蛋白;; Tau蛋白; 神经元
中图分类号:R382.5 文献标志码:A 文章编号:1002-2694(2018)10-0931-05
Advances on the association between Toxoplasma gondii infection and Alzheimer̓s disease
ZHENG Bin, LI Jin-na
Department of Parasitology, Xinxiang Medical University, Henan 453003, China
Fund:Supported by the Programs for Science and Technology Development of Henan Province (No. 172102310404), the Programs for Science and Technology Development of Xinxiang (No. GXGG16017), and the Doctor Start⁃up Fund Research of Xinxiang Medical University (No. 100777)
Abstract

Alzheimer̓s disease (AD) is a progressive neurodegenerative disease, and the pathogenesis of AD has not been fully elucidated. Patients with AD had higher seropositivity rates for anti- Toxoplasma gondii ( T. gondii) IgG antibodies compared to healthy controls. T. gondii infection caused AD-like symptoms (cognitive impairment, memory loss); infected wild-type mice showed major signs of AD including Aβ deposition, pTau expression, and neuronal loss. Results of researches indicate a possible link between T. gondii infection and AD. In this review, we summarized recent advances on the association between T. gondii infection and AD.

Key words: Toxoplasma gondii; Alzheimer̓s disease; beta-amyloid (Aβ);; Tau protein; neuron

阿尔茨海默病(Alzheimer̓s disease, AD)俗称老年痴呆或老年认知障碍, 是老年人常见的一种中枢神经系统退行性疾病。AD的主要临床表现为认知与记忆功能及日常生活能力的进行性减退, 并伴有各种神经精神症状和行为障碍[1]。预计到2050年, 我国将有800~1 200万AD患者。在老龄化日趋显著的情况下, AD已成为严重的社会公共卫生问题[2]。

AD的病理表现主要包括神经细胞外β -淀粉样蛋白(amyloid protein β , Aβ )聚集形成的斑块(老年斑, senile plaque, SP), 神经细胞内Tau蛋白过度磷酸化形成的神经原纤维缠结(neurofibrillary tangle, NFT)以及反应性小胶质细胞活化、神经突营养不良、神经元丢失和突触功能紊乱[3]。AD的发病机制尚未完全阐明, 普遍认为与遗传因素、环境因素(头颅外伤史、炎症反应和病原体感染等)相关[4, 5, 6, 7, 8, 9]。

刚地弓形虫(Toxoplasma gondii)为专性细胞内寄生原虫, 可寄生于人和多种动物的有核细胞内, 导致弓形虫感染或弓形虫病。弓形虫感染后, 其包囊主要位于宿主的嗅球、杏仁核、大脑皮质、海马、小脑和基底核等部位, 这些部位的弓形虫包囊负荷量增多可导致相应的功能异常, 而海马功能的异常与老年痴呆、抑郁症、精神病等神经精神疾病相关[10, 11, 12]。本文对弓形虫感染与AD相关性的研究进展做一综述, 旨在为日后临床上应用抗寄生虫等手段预防和治疗AD提供线索。

1 AD患者的弓形虫感染

Kusbeci等[13]采用ELISA检测土耳其的34名AD患者和37名健康对照者血清中的弓形虫抗体, 结果发现AD患者弓形虫IgG阳性率为44.1%, 对照组为24.3%, 差异有统计学意义。提示AD的发生与弓形虫感染可能相关联。

2 弓形虫感染引发或加重AD样症状

Fekadu等[14]的调查揭示弓形虫感染与精神异常、行为障碍、人格改变等有关联, 丙戊酸(valproic acid)等抗惊厥药物通过抑制脑内弓形虫的繁殖, 达到抗惊厥的效果。对美国20-59岁成年人的调查发现, 弓形虫可能通过掠夺神经元的叶酸而影响人类的认知[15]。Gale等[16]对4 178人进行计算机测试, 发现弓形虫感染人群的生理反应时间、处理事件的速度、短期记忆和注意力等都发生了改变, 弓形虫感染改变了人的认知功能。Mendy等[17]的调查显示老年人的弓形虫血清阳性率与记忆损害有关。对65岁或以上老年人(42名弓形虫血清阳性者和42名阴性者)进行工作记忆测试和心理计量测试, 结果发现弓形虫血清阳性的老年人存在记忆损害、工作记忆效能减退、言语记忆低效、瞬时记忆减少、认知延时等表现[18]。Nimgaonkar等[19]对被调查者的注意力、管理能力、记忆、语言和视觉空间功能等进行连续5年的评估, 结果发现被调查者的弓形虫抗体滴度明显与暂时认知减退相关。即对于老年人群来说, 认知退化与弓形虫感染有关。对133名痴呆患者和95名对照者进行认知评估、弓形虫抗体检测和载脂蛋白E (apolipoprotein E, ApoE, 介导神经元的胆固醇传输, 胆固醇为轴突发育、突触重塑、记忆开发和神经元修复的关键成分)位点测定, 结果发现弓形虫抗体阳性患者无论是否携带ApoE4, 都有高度发展为痴呆的风险[20]。

动物实验发现弓形虫感染后, 小鼠对捕食者猫的尿液的恐惧感、厌恶感消失[21]。弓形虫感染BALB/c小鼠后, 感染鼠的逃避潜伏期明显长于AD鼠, 学习能力减弱; 滞留在目标象限的时间和路程减少, 记忆功能受损[22]。弓形虫Tehran株感染雄性小鼠后, 可引起小鼠类焦虑症状和认知功能受损[23]。C57BL/6小鼠感染弓形虫ME49株后, 感染鼠的空间记忆能力受损、探索新事物的兴趣减退、表现类焦虑症状[24]。弓形虫PRU株感染昆明鼠后, 感染鼠探究新物体的时间明显少于对照组; 感染鼠的逃避潜伏期明显长于对照组[25]。弓形虫感染促进感染大鼠的神经认知特别是记忆障碍的出现[26]。

3 弓形虫感染引发或加重AD样病变
3.1 弓形虫感染引起脑组织Aβ 沉积

用弓形虫ME49株感染C57BL/6小鼠, 感染后15 d, 小鼠脑部可见Aβ 特异性抗体6E10阳性(6E10+)标记的区域, 且与弓形虫包囊共定位。感染后60、90 d, 脑部的其它区域也可见6E10+标记。感染后30 d和90 d脑部皮质区的6E10+标记差异有统计学意义; 海马区的6E10+标记明显增多[24]。Cabral等[27]用弓形虫的Ⅰ 和Ⅲ 型虫株腹腔注射感染3月龄J20雌鼠, 感染后6个月, 感染鼠海马区可见Aβ 斑。

3.2 弓形虫感染诱发脑组织Tau蛋白高度磷酸化

过度磷酸化的Tau 蛋白(pTau)可影响神经元骨架微管蛋白的稳定性, 导致NFT形成。Torres等[24]的研究发现用AT8抗体特异性标记pTau, 弓形虫ME49株感染后15 d, 感染鼠脑内可见pTau标记, 感染后60 d, 标记点增多, 皮质区和海马区的标记明显。Western blot显示, 感染后60 d, AT8抗体特异性识别的蛋白含量增多, 提示pTau的含量增多。

3.3 弓形虫感染损伤脑部神经元

Torres等[24]的研究发现弓形虫感染鼠脑部的NeuN+、TUNEL+标记和弓形虫包囊共同定位于前额皮质区。且随着感染的发展, 脑内NeuN+和TUNEL+标记明显增多。在整个嗅球区, TUNEL+标记明显, 提示嗅球神经元细胞死亡。C57BL/6小鼠腹腔接种弓形虫ME49虫株后3、6周, 感染鼠脑部海马区嗜酸性神经元(细胞体积缩小、胞质嗜酸性、胞核深染)增多, 提示弓形虫感染期神经退行性病变增多[28]。Parlog等[29]的研究揭示弓形虫感染后, 树突棘的长度和密度明显缩减。弓形虫可通过上调宿主细胞内的抗凋亡基因或调整凋亡信号途径, 抑制脑部神经元细胞凋亡[30]。弓形虫通过操纵Ca2+信号途径, 影响神经元对谷氨酸盐的反应, 进而调整相应神经元的功能[31]。

3.4 弓形虫感染影响突触可塑性和神经递质

谷氨酸是人类中枢神经系统中主要的兴奋性递质, N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)是一种重要的谷氨酸受体, 主要参与调节神经元的存活、树突和轴突结构以及突触可塑性的形成。弓形虫感染后15、30 d, 小鼠脑部皮质区和海马区的NMDAR表达明显减少。感染后60 d, NMDAR表达减少更明显。荧光定位显示NMDAR与弓形虫包囊共定位, 提示弓形虫感染与NMDAR丢失相关。Western blot显示, 感染后60 d, NMDAR蛋白含量明显减少[24]。

弓形虫感染鼠脑部的左旋谷氨酸脱羧酶67(L-glutamic acid decarboxylase 67, GAD67)表达增加, GAD67为生产抑制性神经递质γ -氨基丁酸(γ -aminobutyric acid, GABA)的酶之一, 进而影响GABA能的神经传递[24]。Brooks等[32]的研究发现弓形虫ME49虫株感染鼠的大脑中GAD分布弥散程度增高, 突触前末端的GAD丢失, 进而影响GABA能信号途径。GABA 受体分布于杏仁核、海马和额叶等控制焦虑的脑区, 因而GABA生成障碍可引起焦虑反应[33]。

多项研究发现, 弓形虫感染后脑内多巴胺的含量增高, 去甲肾上腺素和5-羟色胺的含量降低[34, 35, 36]。Gatkowska等[37, 38]研究揭示弓形虫感染的细胞分泌多巴胺的量3倍于非感染细胞, 进而通过多巴胺或多巴胺信号途径, 干扰脑的功能(运动、认知、记忆、情绪、学习和奖赏), 影响宿主的行为。

3.5 弓形虫感染引发脑部神经炎症

弓形虫感染激发宿主的免疫反应, 引起脑内免疫细胞和分子分布的改变。患弓形虫脑病(Toxoplasma encephalitis, TE)的小鼠体内的IL-6、IL-1β 、TNF-α 表达上调[39]。离体培养的小鼠神经胶质细胞中, 弓形虫感染的星形胶质细胞分泌IL-1β 、IL-6增加, 小胶质细胞大量分泌IL-10和TNF-α [40]。弓形虫感染后, 中枢神经系统中的炎性因子和介质(TNF-α 、IL-6和IL-1等)增多, 这些因子限制了虫体的复制和扩散, 同时也引起未感染神经元的损害、影响神经递质的功能和突触传递[41, 42]。

Mahmoudvand等[22]的研究结果揭示弓形虫感染AD鼠脑部的IL-1β 、TNF-α 、IFN-γ 和诱导型一氧化氮合酶((inducible nitric oxide synthase, iNOS)的mRNA量明显多于未感染AD鼠; 弓形虫ME49株灌胃感染AD鼠, 感染鼠的促炎症反应增强, 促炎介质TNF-α 、IL-6、CC类趋化因子配体5[chemokine(C-C motif)ligand 5, CCL5]和CXCL-1的生产增多, 明显高于未感染AD鼠[43]。Cabral等[27]的研究发现, 弓形虫Ⅱ 和Ⅲ 型虫株感染鼠脑部CCL5、CXCL-10、IFN-γ 、IL-6和单核细胞趋化蛋白-1(MCP-1) 的含量明显增多。

弓形虫感染后, 未被感染的神经胶质细胞呈现出明显的活跃状态, 尤其是星形胶质细胞活动最为明显[44]。Montacute等[27, 43]的研究发现弓形虫感染后, 感染鼠大脑皮层和海马区活化的小胶质细胞增多。

3.6 弓形虫感染与氧化应激、AD样表现

Leuner等[45]的研究结果揭示弓形虫感染可激活脑部的活性氧(reactive oxygen species, ROS), 诱导产生Aβ 1-42。弓形虫感染引起脑内一氧化氮(NO)大量产生、神经胶质细胞激活及凋亡, 导致严重的神经病变。感染组的谷胱甘肽还原酶和神经元特异性烯醇酶(neuron specific enolase, NSE)的表达明显增高, 超氧化物歧化酶(superoxide dismutase, SOD)的活性降低。氧化应激(oxidative stress, OS)后, 胞核和胞质的8羟基2脱氧鸟苷(8-hydroxy-2'-deoxyguanosine, 8-OHdG)着色加深。由此推测弓形虫介导的OS在TE的神经病理改变中发挥重要作用。也提示增高的NO和胶质细胞凋亡促成了OS相关的TE病变[46]。

4 结 语

血清学调查、行为学分析、病理学检测和动物试验等多项研究的结果均提示弓形虫感染与AD的发生、发展相关。但也有报道AD人群弓形虫IgG血清阳性率(41%)与健康对照人群(33%)差异无统计学意义[47]。有研究发现弓形虫感染可以抑制小鼠脑部神经元退变和学习记忆能力损害[48]。用弓形虫Ⅱ 型虫株腹腔注射感染3月龄J20雌鼠, 感染后6个月, 感染鼠海马区Aβ 斑荷量明显少于对照组[27]。还有研究揭示弓形虫ME49株感染AD小鼠后, 感染鼠脑部招募的骨髓来源单核细胞对Aβ 的吞噬增多, 脑部对Aβ 降解的酶增多, 对Aβ 的降解增加, 因而海马区的Aβ 斑荷量减少[49]。弓形虫感染对AD症状及病变的影响有明显不同的研究结果, 原因可能在于AD的建模方式、实验动物的种类、弓形虫的感染途径、虫株和感染剂量不同所致[50]。

不仅弓形虫感染与AD的发生、发展有关联, 利什曼原虫感染后, 小鼠大脑皮层的Ser396 pTau含量增加, 高级糖基化终末产物受体(receptor for advanced glycation endproducts, RAGE)的含量明显增加, 而脑部的RAGE有助于神经变性[51, 52]。

寄生虫感染和AD相关性的研究, 解释了部分AD的发病机制, 也为日后临床上应用抗寄生虫等手段预防和治疗AD提供了线索。

The authors have declared that no competing interests exist.

参考文献
[1] Alzheimer̓s Association. 2016 Alzheimer̓s disease facts and figures[J]. Alzheimers Dement, 2016, 12(4): 459-509. [本文引用:1]
[2] Shubhakaran KP, Khichar RJ. Dementia in China: current status[J]. Neurology, 2014, 82(14): 1291. DOI: DOI:10.1212/WNL.0000000000000233 [本文引用:1]
[3] Weinreb O, Mand el S, Bar-Am O, et al. Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic agents for Alzheimer̓s disease: a tribute to Moussa Youdim[J]. J Neural Transm (Vienna), 2011, 118(3): 479-492. DOI: DOI:10.1007/s00702-011-0597-6 [本文引用:1]
[4] Lim C, Hammond CJ, Hingley ST, et al. Chlamydia pneumoniae infection of monocytes in vitro stimulates innate and adaptive immune responses relevant to those in Alzheimer̓s disease[J]. J Neuroinflammation, 2014, 11: 217. DOI: DOI:10.1186/s12974-014-0217-0 [本文引用:1]
[5] 杨新玲, 刘雪晴, 杨杰民. 肺炎衣原体感染与阿尔茨海默病的关系[J]. 中国人兽共患病学报, 2013, 29(2): 195-198. DOI: DOI:10.969/cjz.j.issn1002-2694.2013.01.020 [本文引用:1]
[6] Kountouras J, Boziki M, Zavos C, et al. A potential impact of chronic Helicobacter pylori infection on Alzheimer̓s disease pathobiology and course[J]. Neurobiol Aging, 2012, 33: e3-e4. DOI: DOI:10.1016/j.neurobiolaging.2012.01.003 [本文引用:1]
[7] Prand ota J. Possible link between Toxoplasma Gondii and the anosmia associated with neurodegenerative diseases[J]. Am J Alzheimers Dis, 2014, 29: 205-214. DOI: DOI:10.1177/1533317513517049 [本文引用:1]
[8] Borjabad A, Volsky DJ. Common transcriptional signatures in brain tissue from patients with HIV-associated neurocognitive disorders, Alzheimer̓s disease, and Multiple Sclerosis[J]. J Neuroimmune Pharmacol, 2012, 7: 914-926. DOI: DOI:10.1007/s11481-012-9409-5 [本文引用:1]
[9] Lurain NS, Hanson BA, Martinson J, et al. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer̓s disease[J]. J Infect Dis, 2013, 208: 564-572. DOI: DOI:10.1093/infdis/jit210 [本文引用:1]
[10] Berenreiterová M, Flegr J, Kuběna AA, et al. The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis[J]. PLoS One, 2011, 6(12): e28925. DOI: DOI:10.1371/journal.pone.0028925 [本文引用:1]
[11] Vyas A, Sapolsky R. Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain[J]. Folia Parasitol (Praha), 2010, 57(2): 88-94. [本文引用:1]
[12] Torrey EF, Bartko JJ, Yolken RH. Toxoplasma gondii and other risk factors for schizophrenia: an update[J]. Schizophr Bull, 2012, 38(3): 642-647. DOI: DOI:10.1093/schbul/sbs043 [本文引用:1]
[13] Kusbeci OY, Miman O, Yaman M, et al. Could Toxoplasma gondii have any role in Alzheimer disease[J]. Alzheimer Dis Assoc Disord, 2011, 25(1): 1-3. DOI: DOI:10.1097/WAD.0b013e3181f73bc2 [本文引用:1]
[14] Fekadu A, Shibre T, Cleare AJ. Toxoplasmosis as a cause for behaviour disorders-overview of evidence and mechanisms[J]. Folia Parasitol (Praha), 2010, 57(2): 105-113. [本文引用:1]
[15] Berrett AN, Gale SD, Erickson LD, et al. Toxoplasma gondii moderates the association between multiple Folate-Cycle factors and cognitive function in U. S. adults[J]. Nutrients, 2017, 9(6): 564. DOI: DOI:10.3390/nu9060564 [本文引用:1]
[16] Gale SD, Brown BL, Erickson LD, et al. Association between latent toxoplasmosis and cognition in adults: a cross-sectional study[J]. Parasitology, 2015, 142(4): 557-565. DOI: DOI:10.1017/S0031182014001577 [本文引用:1]
[17] Mendy A, Vieira ER, Albatineh AN, et al. Immediate rather than delayed memory impairment in older adults with latent toxoplasmosis[J]. Brain Behav Immun, 2015, 45: 36-40. DOI: DOI:10.1016/j.bbi.2014.12.006 [本文引用:1]
[18] Gajewski PD, Falkenstein M, Hengstler JG, et al. Toxoplasma gondii impairs memory in infected seniors[J]. Brain Behav Immun, 2014, 36: 193-199. DOI: DOI:10.1016/j.bbi.2013.11.019 [本文引用:1]
[19] Nimgaonkar VL, Yolken RH, Wang T, et al. Temporal cognitive decline associated with exposure to infectious agents in a population-based, aging Cohort[J]. Alzheimer Dis Assoc Disord, 2016, 30(3): 216-222. DOI: DOI:10.1097/WAD.00000000-00000133 [本文引用:1]
[20] Yahya RS, Awad SI, El-Baz HA, et al. Impact of ApoE genotypes variations on Toxoplasma patients with dementia[J]. J Clin Neurosci, 2017, 39: 184-188. DOI: DOI:10.1016/j.jocn.2017.01.009 [本文引用:1]
[21] House PK, Vyas A, Sapolsky R. Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats[J]. PLoS One, 2011, 6(8): e23277. DOI: DOI:10.1371/journal.pone.0023277 [本文引用:1]
[22] Mahmoudvand H, Sheibani V, Shojaee S, et al. Toxoplasma gondii infection potentiates cognitive impairments of Alzheimer̓s Disease in the BALB/c mice[J]. J Parasitol, 2016, 102(6): 629-635. DOI: DOI:10.1645/16-28 [本文引用:2]
[23] Mahmoudvand H, Ziaali N, Aghaei I, et al. The possible association between Toxoplasma gondii infection and risk of anxiety and cognitive disorders in BALB/c mice[J]. Pathog Glob Health, 2015, 109(8): 369-376. DOI: DOI:10.1080/20477724.2015.1117742 [本文引用:1]
[24] Torres L, Robinson SA, Kim DG, et al. Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer̓s disease in wild-type, C57BL/6 mice[J]. J Neuroinflammation, 2018, 15(1): 57. DOI: DOI:10.1186/s12974-018-1086-8 [本文引用:6]
[25] 周永华, 王小波, 蒋守富, 等. 隐性弓形虫感染小鼠的学习记忆能力障碍研究[J]. 中国寄生虫学与寄生虫病杂志, 2011, 29(5): 333-338. [本文引用:1]
[26] Daniels BP, Sestito SR, Rouse ST. An expand ed task battery in the Morris water maze reveals effects of Toxoplasma gondii infection on learning and memory in rats[J]. Parasitol Int, 2015, 64(1): 5-12. DOI: DOI:10.1016/j.parint.2014.09.002 [本文引用:1]
[27] Cabral CM, McGovern KE, MacDonald WR, et al. Dissecting amyloid beta deposition using distinct strains of the neurotropic parasite Toxoplasma gondii as a novel tool[J]. ASN Neuro, 2017, 9(4): 1759091417724915. DOI: DOI:10.1177/1759091417724915 [本文引用:4]
[28] Hwang YS, Shin JH, Yang JP, et al. Characteristics of infection immunity regulated by Toxoplasma gondii to maintain chronic infection in the brain[J]. Front Immunol, 2018, 9: 158. DOI: DOI:10.3389/fimmu.2018.00158 [本文引用:1]
[29] Parlog A, Harsan LA, Zagrebelsky M, et al. Chronic murine toxoplasmosis is defined by subtle changes in neuronal connectivity[J]. Dis Model Mech, 2014, 7(4): 459-469. DOI: DOI:10.1242/dmm.014183 [本文引用:1]
[30] Vutova P, Wirth M, Hippe D, et al. Toxoplasma gondii inhibits Fas/CD95-triggered cell death by inducing aberrant processing and degradation of caspase 8[J]. Cell Microbiol, 2007, 9(6): 1556-1570. DOI: DOI:10.1111/j.1462-5822.2007.00893.x [本文引用:1]
[31] Haroon F, Hndel U, Angenstein F, et al. Toxoplasma gondii actively inhibits neuronal function in chronically infected mice[J]. PLoS One, 2012, 7(4): e35516. DOI: DOI:10.1371/journal.pone.0035516 [本文引用:1]
[32] Brooks JM, Carrillo GL, Su J, et al. Toxoplasma gondii infections alter GABAergic synapses and signaling in the central nervous system[J]. MBio, 2015, 6(6): e01428-15. DOI: DOI:10.1128/mBio.01428-15 [本文引用:1]
[33] Kaushik M, Lamberton PH, Webster JP. The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system[J]. Horm Behav, 2012, 62(3): 191-201. DOI: DOI:10.1016/j.yhbeh.2012.04.002 [本文引用:1]
[34] Parlog A, Schlüter D, Dunay IR. Toxoplasma gondii-induced neuronal alterations[J]. Parasite Immunol, 2015, 37(3): 159-170. DOI: DOI:10.1111/pim.12157 [本文引用:1]
[35] Mahmoud ME, Fereig R, Nishikawa Y. Involvement of host defense mechanisms against Toxoplasma gondii infection in anhedonic and despair-Like behaviors in mice[J]. Infect Immun, 2017, 85(4): e00007-17. DOI: DOI:10.1128/IAI.00007-17 [本文引用:1]
[36] Martin HL, Alsaady I, Howell G, et al. Effect of parasitic infection on dopamine biosynthesis in dopaminergic cells[J]. Neuroscience, 2015, 306: 50-62. DOI: DOI:10.1016/j.neuroscience.2015.08.005 [本文引用:1]
[37] Gatkowska J, Wieczorek M, Dziadek B, et al. Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice[J]. Exp Parasitol, 2013, 133(1): 1-7. DOI: DOI:10.1016/j.exppara.2012.10.005 [本文引用:1]
[38] Prand ovszky E, Gaskell E, Martin H, et al. The neurotropic parasite Toxoplasma gondii increases dopamine metabolism[J]. PLoS One, 2011, 6(9): e23866. DOI: DOI:10.1371/journal.pone.0023866 [本文引用:1]
[39] Zhang YH, Chen H, Chen Y, et al. Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis[J]. Parasit Vectors, 2014, 7: 372. DOI: DOI:10.1186/1756-3305-7-372 [本文引用:1]
[40] Fischer HG, Nitzgen B, Reichmann G, et al. Cytokine responses induced by Toxoplasma gondii in astrocytes and microglial cells[J]. Eur J Immunol, 1997, 27(6): 1539-1548. DOI: DOI:10.1002/eji.1830270633 [本文引用:1]
[41] Munoz M, Liesenfeld O, Heimesaat MM. Immunology of Toxoplasma gondii[J]. Immunol Rev, 2011, 240(1): 269-285. DOI: DOI:10.1111/j.1600-065X.2010.00992.x [本文引用:1]
[42] McCusker RH, Kelley KW. Immune-neural connections: how the immune system̓s response to infectious agents influences behavior[J]. J Exp Biol, 2013, 216(Pt 1): 84-98. DOI: DOI:10.1242/jeb.073411 [本文引用:1]
[43] Montacute R, Foley K, Forman R, et al. Enhanced susceptibility of triple transgenic Alzheimer̓s disease (3×Tg-AD) mice to acute infection[J]. J Neuroinflammation, 2017, 14(1): 50. DOI: DOI:10.1186/s12974-017-0826-5 [本文引用:2]
[44] Carruthers VB, Suzuki Y. Effects of Toxoplasma gondii infection on the brain[J]. Schizophr Bull, 2007, 33(3): 745-751. DOI: DOI:10.1093/schbul/sbm008 [本文引用:1]
[45] Leuner K, Schütt T, Kurz C, et al. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation[J]. Antioxid Redox Signal, 2012, 16(12): 1421-1433. DOI: DOI:10.1089/ars.2011.4173 [本文引用:1]
[46] Dincel GC, Atmaca HT. Role of oxidative stress in the pathophysiology of Toxoplasma gondii infection[J]. Int J Immunopathol Pharmacol, 2016, 29(2): 226-240. DOI: DOI:10.1177/0394632016638668 [本文引用:1]
[47] Perry CE, Gale SD, Erickson L, et al. Seroprevalence and serointensity of latent Toxoplasma gondii in a sample of elderly adults with and without Alzheimer Disease[J]. Alzheimer Dis Assoc Disord, 2016, 30(2): 123-126. DOI: DOI:10.1097/WAD.0000000000000108 [本文引用:1]
[48] Jung BK, Pyo KH, Shin KY, et al. Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer̓s disease[J]. PLoS One, 2012, 7(3): e33312. DOI: DOI:10.1371/journal.pone.0033312 [本文引用:1]
[49] Möhle L, Israel N, Paarmann K, et al. Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes[J]. Acta Neuropathol Commun, 2016, 4(1): 25. DOI: DOI:10.1186/s40478-016-0293-8 [本文引用:1]
[50] Worth AR, Lymbery AJ, Thompson RC. Adaptive host manipulation by Toxoplasma gondii: fact or fiction[J]. Trends Parasitol, 2013, 29(4): 150-155. DOI: DOI:10.1016/j.pt.2013.01.004 [本文引用:1]
[51] Gasparotto J, Senger MR, Kunzler A, et al. Increased tau phosphorylation and receptor for advanced glycation end products (RAGE) in the brain of mice infected with Leishmania amazonensis[J]. Brain Behav Immun, 2015, 43: 37-45. DOI: DOI:10.1016/j.bbi.2014.06.204 [本文引用:1]
[52] Arancio O, Zhang HP, Chen X, et al. RAGE potentiates A beta-induced perturbation of neuronal function in transgenic mice[J]. EMBO J, 2004, 23(20): 4096-4105. DOI: DOI:10.1038/sj.emboj.7600415 [本文引用:1]