TY  - JOUR
A1  - Grotemeyer, Alexander
A1  - Fischer, Judith F.
A1  - Koprich, James B.
A1  - Brotchie, Jonathan M.
A1  - Blum, Robert
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
T1  - Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease
JF  - Journal of Neuroinflammation
N2  - Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.
KW  - neurodegeneration
KW  - movement disorder
KW  - neuroinflammation
KW  - Parkinson’s disease
KW  - inflammasome
KW  - dopaminergic cells
KW  - NLRP3
KW  - MCC950
KW  - microglia
KW  - T cells
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357652
VL  - 20
ER  - 
TY  - JOUR
A1  - Badr, Mohammad
A1  - McFleder, Rhonda L.
A1  - Wu, Jingjing
A1  - Knorr, Susanne
A1  - Koprich, James B.
A1  - Hünig, Thomas
A1  - Brotchie, Jonathan M.
A1  - Volkmann, Jens
A1  - Lutz, Manfred B.
A1  - Ip, Chi Wang
T1  - Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson’s disease mice
JF  - Journal of Neuroinflammation
N2  - Background
Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment.

Methods
Using the AAV1/2-A53T-α-synuclein Parkinson’s disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage.

Results
CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson’s disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson’s disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson’s disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson’s disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration.

Conclusions
Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson’s disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson’s disease patients.
KW  - Parkinson’s disease
KW  - neuroinflammation
KW  - T cells
KW  - regulatory T cells
KW  - neuroprotection
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300580
VL  - 19
ER  -