Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils.
Animals
Animals, Newborn
Brain Chemistry
Connectome
Corpus Striatum
Dose-Response Relationship, Drug
Female
Humans
Iron
/ administration & dosage
Male
Memory Disorders
/ chemically induced
Mice, Inbred C57BL
Microglia
/ pathology
Microinjections
Motor Activity
/ drug effects
Synucleinopathies
/ metabolism
alpha-Synuclein
/ administration & dosage
Parkinson's disease
alpha-synuclein
alpha-synuclein propagation
alpha-synuclein seeding
iron dyshomeostasis
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
22
06
2021
received:
02
02
2021
accepted:
23
06
2021
pubmed:
28
6
2021
medline:
20
11
2021
entrez:
27
6
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
alpha-Synuclein
0
Iron
E1UOL152H7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
554-573Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
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