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Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils.
- Source :
-
Journal of neurochemistry [J Neurochem] 2021 Nov; Vol. 159 (3), pp. 554-573. Date of Electronic Publication: 2021 Aug 02. - Publication Year :
- 2021
-
Abstract
- Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.<br /> (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)
- Subjects :
- Animals
Animals, Newborn
Connectome
Corpus Striatum
Dose-Response Relationship, Drug
Female
Humans
Iron administration & dosage
Male
Memory Disorders chemically induced
Memory Disorders psychology
Mice, Inbred C57BL
Microglia pathology
Microinjections
Motor Activity drug effects
alpha-Synuclein administration & dosage
Mice
Brain Chemistry
Iron pharmacology
Synucleinopathies metabolism
Synucleinopathies pathology
alpha-Synuclein metabolism
alpha-Synuclein toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 159
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34176164
- Full Text :
- https://doi.org/10.1111/jnc.15461