Chronic Toxoplasma Gondii Infection Enhances Β-Amyloid Phagocytosis and Clearance by Recruited Monocytes

Möhle et al. Acta Neuropathologica Communications (2016) 4:25 DOI 10.1186/s40478-016-0293-8 RESEARCH Open Access Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes Luisa Möhle1, Nicole Israel2, Kristin Paarmann3,12,13, Markus Krohn3, Sabine Pietkiewicz4, Andreas Müller2,5, Inna N. Lavrik4, Jeffrey S. Buguliskis6, Björn H. Schott7,8,9, Dirk Schlüter1,7, Eckart D. Gundelfinger7,10,11,12, Dirk Montag13, Ulrike Seifert2, Jens Pahnke3,14,15 and Ildiko Rita Dunay1,7* Abstract Introduction: Alzheimer’s disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD. Results: Chronic infection with T. gondii was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2hi Ly6Chi monocytes, CCR2+ Ly6Cint, and CCR2+ Ly6Clow mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo. The F4/80+ Ly6Clow macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2+ Ly6Chi monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits β1i/LMP2, β2i/MECL-1,andβ5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance. Conclusions: Our results indicate that chronic Toxoplasma infection ameliorates β-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6Chi monocytes and by enhancement of phagocytosis and degradation of soluble Aβ. Our findings provide evidence for a modulatory role of inflammation-induced Aβ phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD. Keywords: Alzheimer’s disease, Toxoplasma gondii, Chronic infection, Ly6Chi monocytes, Aβ clearance * Correspondence: [email protected] 1Institute for Medical Microbiology and Hospital Hygiene, University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany 7Center for Behavioral Brain Sciences (CBBS), University of Magdeburg, Magdeburg, Germany Full list of author information is available at the end of the article © 2016 Möhle et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Möhle et al. Acta Neuropathologica Communications (2016) 4:25 Page 2 of 19 Introduction common sporadic form of AD primarily occurs in the Alzheimer’s disease (AD) is the most prevalent cause of elderly, and older age is also associated with elevated dementia in the elderly, affecting more than 15 million susceptibility to infectious diseases [39], and an in- people worldwide [1]. Although AD was first described creased probability of having accumulated dormant in- more than a century ago, the exact pathomechanisms of fections, including toxoplasmosis [40–42]. this disorder are still not fully understood. According to Toxoplasmosis, caused by the obligate intracellular the widely accepted amyloid cascade hypothesis [2], the protozoan parasite Toxoplasma (T.) gondii, is a worldwide amyloid precursor protein (APP) is cleaved by β- and γ- zoonosis with high medical relevance [40]. Serologic secretases, and the resulting Aβ40 and Aβ42 peptides ac- prevalence data suggest that the geographical distribution cumulate as fibrils and plaques, due to their highly of the infection varies between 20 and 90 %, depending hydrophobic nature [3–5]. However, in aging individuals mainly on culinary habits and hygiene. Moreover, the in- and in AD patients it is not overproduction, but reduced fection rate strongly increases with age [43], as latent clearance of β-amyloid (Aβ) that is thought to contribute T. gondii infection is associated with lifelong parasite per- to disease progression [6]. Specific transporters at the sistence and typically remains clinically asymptomatic in blood–brain barrier were discovered to transport Aβ immunocompetent individuals. However, recent studies – and their insufficient function leads to intracerebral Aβ by our laboratory and others – indicate an ongoing basal accumulation and plaque formation [7–10]. Clearance inflammation in the CNS following chronic T. gondii in- by the brain’s phagocytic system is also known to play fection in rodents [44–46]. The subtle neuromodulatory an important role in limiting disease progression. At capacity of the parasite in humans and mice has also been first, microglia cells become activated, but later fall into an area of recent investigation [47]. Prominent features of a state of senescence, thus failing to effectively remove cerebral toxoplasmosis in animal models are the activation intracellular and extracellular Aβ – a development that of glia and recruitment of peripheral immune cells to the is paralleled by ongoing neuroinflammation [11–13]. Ul- CNS [18, 48, 49]. Recruited Ly6Chi monocytes co- timately, severe neurodegeneration leads to cognitive im- expressing C-C chemokine receptor type 2 (CCR2) [50] are pairments and behavioral alterations [14]. critical to governing acute and chronic stages of infection The role of innate immune cells has been discussed ex- [18, 23, 51–53]. Principally, we have recently described the tensively in an attempt to untangle their beneficial and contribution of Ly6Cint monocyte-derived dendritic cells detrimental contributions in brain homeostasis and path- and Ly6Clow monocyte-derived macrophages to parasite ology [15–18]. Previously, all phagocytic cells in the brain control upon chronic toxoplasmosis in the CNS [23]. have been termed “microglia”, until it recently became The role of T. gondii in the development and course of evident that resident microglia develop from yolk sac AD is currently debated. Kusbeci et al. reported increased macrophages and populate the CNS during early fetal de- seroprevalence of anti-T. gondii IgG in a small group of velopment [19], whereas distinct populations of bone AD patients, suggesting an implication of the parasite in marrow-derived mononuclear cells can enter the adult AD pathogenesis [54], but these findings could not be rep- CNS under inflammatory and even under steady-state licated in another study [55]. Animal studies have sug- conditions [20–22]. Furthermore, infiltrating myeloid- gested that T. gondii infection may actually be able to derived Ly6Chi CCR2+ monocytes also give rise to brain prevent neurodegeneration [56, 57] and can even reduce macrophages [17, 23–25]. Subsequent differentiation of plaque burden and prevent memory decline [58]. The lat- resident and recruited innate immune cells has revealed ter studies suggest that T. gondii may actually play a pro- distinct contributions of each subset under various tective rather than a detrimental role in AD. However, pathological conditions [22]. Resident microglia accu- they do not address the underlying mechanisms of plaque mulate directly around Aβ plaques, and contribute to reduction. In the present study, we investigated how AD Aβ clearance in the early phase of AD development. progression is influenced by the boosted presence of mye- Later on, their role becomes a detrimental one, as they loid cells in the CNS in latent toxoplasmosis. promote neurodegeneration by pro-inflammatory Our data reveal that upon chronic Toxoplasma infection, cytokine production [26]. Interestingly, bone marrow- recruited mononuclear cells are capable of ameliorating derived mononuclear cells recruited to the CNS con- plaque burden in a murine model of cerebral β-amyloidosis tribute to repair after spinal cord injury [27] as well as through Aβ phagocytosis and increased degradation. Aβ uptake and plaque elimination [28–30]. Several studies have described that AD is exacerbated Materials and methods by repeated or chronic systemic inflammation as well as Animal models by several infections in humans and different murine All animal experiments were approved according to models [31–36]. It has even been speculated that specific German and European legislation by the local au- pathogens may be causative in AD [37, 38]. The most thorities. Experiments were conducted with 8 weeks Möhle

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