Aage Kristian Olsen Alstrup

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Documents

DOI

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 (alpha-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 alpha-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [C-11](R)PK11195, to image brain microglial activation and (+)-alpha-[C-11]dihydrotetrabenazine ([C-11]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Gottingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T alpha-syn or green fluorescent protein (GFP) into the SN (4 rAAV-alpha-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 alpha-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [C-11]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [C-11](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the alpha-syn group than the control animals. We conclude that mutant alpha-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 alpha-syn in the absence of dopamine neuron degeneration.

Original languageEnglish
Article number22060
JournalSynapse
Volume72
Issue12
Number of pages12
ISSN0887-4476
DOIs
Publication statusPublished - Dec 2018

    Research areas

  • [C-11](R)PK11195, adeno-associated viral vectors, alpha-synuclein, animal model, inflammation, minipig, Parkinson's disease, POSITRON-EMISSION-TOMOGRAPHY, VECTOR-MEDIATED OVEREXPRESSION, CEREBRAL METABOLIC-RATE, TUMOR-NECROSIS-FACTOR, PROTEIN 18 KDA, PARKINSONS-DISEASE, MICROGLIAL ACTIVATION, SUBSTANTIA-NIGRA, DOPAMINERGIC-NEURONS, ALZHEIMERS-DISEASE

See relations at Aarhus University Citationformats

Download statistics

No data available

ID: 135269232