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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Thea Pinholt Lillethorup
  • Andreas Nørgaard Glud
  • Natalie Landeck
  • Aage Kristian Olsen Alstrup
  • Steen Jakobsen
  • Kim Vang
  • Doris J. Doudet
  • David J. Brooks
  • Deniz Kirik
  • Rainer Hinz
  • Jens Christian Sørensen
  • Anne M. Landau
Organisations
External organisations
  • Aarhus University
  • University of British Columbia
  • Imperial College London
  • University of Newcastle upon Tyne
  • University of Manchester
  • Aarhus University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • adeno-associated viral vectors, alpha-synuclein, animal model, inflammation, minipig, Parkinson’s disease, [C](R)PK11195
Original languageEnglish
Article numbere22060
JournalSynapse
Volume72
Issue number12
Early online date2018 Jul 15
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes