Defining the contribution of neuroinflammation to Parkinson’s disease in humanized immune system mice

Gunjan Dhawan Manocha, Angela Marie Floden, Kendra Lynn Puig, Kumi Nagamoto-Combs, Clemens R. Scherzer, Colin Kelly Combs

Reactive microglia have been associated with the histological changes that occur in Parkinson's disease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson's disease have not been fully defined. In order to improve understanding of the role of neuroinflammation in Parkinson's disease, we employed the MPTP injection model using humanized CD34+ mice along with age-matched C57BL/6 mice. NSG mice engrafted with hu-CD34+ hematopoietic stem cells were injected with MPTP to quantify cytokine changes, neuron loss, gliosis, and behavioral dysfunction. The mice were also treated with or without the calcineurin/NFAT inhibitor, FK506, to determine whether modulating the immune response could attenuate disease. MPTP injections produced impairment of motor performance, increased microgliosis, elevated brain cytokine levels, and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum of both humanized CD34+ mice and C57BL/6 mice with a strikingly different profile of human versus mouse cytokine elevations observed in each. Interestingly, FK506 injections significantly attenuated the MPTP-induced effects in the humanized CD34+ mice compared the C57BL/6 mice. In addition, analyses of human plasma from Parkinson's disease donors compared to age-matched, healthy controls demonstrated an increase in a number of pro-inflammatory cytokines in female patients similar to that observed in MPTP-injected female CD34+ mice. This study demonstrates for the first time, induction of Parkinson's disease-like symptoms in female humanized CD34+ mice using MPTP. The profile of cytokine changes in the serum and brains of the humanized CD34+ mice following MPTP injection differed significantly from that occurring in the more commonly used C57BL/6 strain of mice. Moreover, several cytokine elevations observed in the MPTP injected humanized CD34+ mice were similarly increased in plasma of PD patients suggesting that these mice offer the more relevant model for the inflammatory aspects of human disease. Consistent with this, the effects of MPTP on loss of tyrosine hydroxylase immunoreactivity, loss of motor strength, and increase in proinflammatory cytokines were attenuated using an immunosuppressant drug, FK506, in the humanized CD34+ but not the C57BL/6 mice. Collectively, these findings suggest that MPTP injected, humanized CD34+ mice represent a more accurate model for assessing inflammatory changes in PD.