RT Journal Article
SR Electronic
T1 Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.30.925883
DO 10.1101/2020.01.30.925883
A1 Valerie Joers
A1 Gunasingh Masilamoni
A1 Doty Kempf
A1 Alison R Weiss
A1 Travis Rotterman
A1 Benjamin Murray
A1 Gul Yalcin-Cakmakli
A1 Ronald J Voll
A1 Mark M Goodman
A1 Leonard Howell
A1 Jocelyne Bachevalier
A1 Stefan Green
A1 Ankur Naqib
A1 Maliha Shaikh
A1 Phillip Engen
A1 Ali Keshavarzian
A1 Christopher J Barnum
A1 Jonathon A Nye
A1 Yoland Smith
A1 Malú Gámez Tansey
YR 2020
UL http://biorxiv.org/content/early/2020/01/31/2020.01.30.925883.abstract
AB 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. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.