Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series

NEUROBIOLOGY OF DISEASE

卷:144

Article

Joers, Valerie^1,2,3  Masilamoni, Gunasingh²  Kempf, Doty²  Weiss, Alison R.^2,4,5  Rotterman, Travis M.^3,6  Murray, Benjamin³  Yalcin-Cakmakli, Gul^2,7  Voll, Ronald J.^2,8  Goodman, Mark M.^2,8  Howell, Leonard^2,8  Bachevalier, Jocelyne^2,5  Green, Stefan J.^9,10  Naqib, Ankur¹¹  Shaikh, Maliha¹¹  Engen, Phillip A.¹¹  Keshavarzian, Ali¹¹  Barnum, Christopher J.¹²  Nye, Jonathon A.²  Smith, Yoland^2,13  Tansey, Malu G.^1,3 

[1] Univ Florida, Coll Med, Ctr Translat Res Neurodegenerat Dis, Gainesville, FL USA

[2] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA

[3] Emory Univ, Dept Physiol, Atlanta, GA 30322 USA

[4] Oregon Natl Primate Res Ctr, Dept Neurosci, Hillsboro, OR USA

[5] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA

[6] Georgia Inst Technol, Sch Biol Sci, Atlanta, GA USA

[7] Hacettepe Univ, Dept Neurol, Ankara, Turkey

[8] Emory Univ, Dept Radiol & Imaging Sci, Atlanta, GA 30322 USA

[9] Univ Illinois, Res Resources Ctr, Sequencing Core, Chicago, IL USA

[10] Univ Illinois, Dept Biol Sci, Chicago, IL 60680 USA

[11] Rush Univ, Med Ctr, Div Gastroenterol, Dept Internal Med, Chicago, IL USA

[12] INmuneBio Inc, La Jolla, CA USA

[13] Emory Univ, Dept Neurol, Atlanta, GA USA

关键词: Parkinson's disease;    MPTP;    Tumor necrosis factor;    Rhesus monkey;    Inflammation;    Sex differences;    Microglia phenotypes;    XPro1595;    Microbiota;    Nonmotor symptoms;   

DOI  :  10.1016/j.nbd.2020.105027

来源: Elsevier

【 摘 要 】

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a gold standard model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [F-18]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [F-18]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.