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In vivo quantification of glial activation in minipigs overexpressing human α-synuclein

Lillethorup, Thea Pinholt ; Glud, Andreas Nørgaard ; Landeck, Natalie LU ; Alstrup, Aage Kristian Olsen ; Jakobsen, Steen ; Vang, Kim ; Doudet, Doris J. ; Brooks, David J. ; Kirik, Deniz LU and Hinz, Rainer , et al. (2018) In Synapse 72(12).
Abstract

Parkinson’s disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson’s disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [11C](R)PK11195, to image brain microglial activation and (+)-α-[11C]dihydrotetrabenazine ([11C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen... (More)

Parkinson’s disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson’s disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [11C](R)PK11195, to image brain microglial activation and (+)-α-[11C]dihydrotetrabenazine ([11C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T α-syn or green fluorescent protein (GFP) into the SN (4 rAAV-α-syn, 4 rAAV-GFP, 5 non-injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and α-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [11C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [11C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the α-syn group than the control animals. We conclude that mutant α-syn expression in the SN resulted in microglial activation in multiple sub- and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of α-syn in the absence of dopamine neuron degeneration.

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Contribution to journal
publication status
published
subject
keywords
adeno-associated viral vectors, alpha-synuclein, animal model, inflammation, minipig, Parkinson’s disease, [C](R)PK11195
in
Synapse
volume
72
issue
12
article number
e22060
publisher
Wiley-Liss Inc.
external identifiers
  • scopus:85052756444
  • pmid:30009467
ISSN
0887-4476
DOI
10.1002/syn.22060
language
English
LU publication?
yes
id
bf2d328c-0378-4533-9938-f34c08fa2b60
date added to LUP
2018-10-05 14:30:12
date last changed
2020-06-24 05:17:18
@article{bf2d328c-0378-4533-9938-f34c08fa2b60,
  abstract     = {<p>Parkinson’s disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson’s disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [<sup>11</sup>C](R)PK11195, to image brain microglial activation and (+)-α-[<sup>11</sup>C]dihydrotetrabenazine ([<sup>11</sup>C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T α-syn or green fluorescent protein (GFP) into the SN (4 rAAV-α-syn, 4 rAAV-GFP, 5 non-injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and α-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [<sup>11</sup>C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [<sup>11</sup>C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the α-syn group than the control animals. We conclude that mutant α-syn expression in the SN resulted in microglial activation in multiple sub- and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of α-syn in the absence of dopamine neuron degeneration.</p>},
  author       = {Lillethorup, Thea Pinholt and Glud, Andreas Nørgaard and Landeck, Natalie and Alstrup, Aage Kristian Olsen and Jakobsen, Steen and Vang, Kim and Doudet, Doris J. and Brooks, David J. and Kirik, Deniz and Hinz, Rainer and Sørensen, Jens Christian and Landau, Anne M.},
  issn         = {0887-4476},
  language     = {eng},
  month        = {07},
  number       = {12},
  publisher    = {Wiley-Liss Inc.},
  series       = {Synapse},
  title        = {In vivo quantification of glial activation in minipigs overexpressing human α-synuclein},
  url          = {http://dx.doi.org/10.1002/syn.22060},
  doi          = {10.1002/syn.22060},
  volume       = {72},
  year         = {2018},
}