Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils

Autor: Stefan Becker, Shuyu Zhang, Karina Joppe, Anna-Elisa Roser, Hazem El DeBakey, Mathias Bähr, Mojan Parvaz, Lars Tatenhorst, Paul Lingor, Eleonora Carboni, Chi Wang Ip, Katarina Vogel-Mikuš, Markus Zweckstetter, Lucas Caldi Gomes
Rok vydání: 2021
Předmět:
administration & dosage [Iron]
Male
Parkinson's disease
Synucleinopathies
alpha-synuclein
animal diseases
administration & dosage [alpha-Synuclein]
Striatum
Biochemistry
chemistry.chemical_compound
Carbonyl iron
metabolism [alpha-Synuclein]
metabolism [Synucleinopathies]
Microglia
Chemistry
pathology [Microglia]
chemically induced [Memory Disorders]
alpha-synuclein seeding
pharmacology [Iron]
Cell biology
medicine.anatomical_structure
Stereotactic injection
alpha-Synuclein
Female
Microinjections
Iron
Central nervous system
Motor Activity
toxicity [alpha-Synuclein]
Cellular and Molecular Neuroscience
medicine
Connectome
Animals
Humans
ddc:610
Alpha-synuclein
Brain Chemistry
Memory Disorders
Dose-Response Relationship
Drug
drug effects [Motor Activity]
iron dyshomeostasis
medicine.disease
In vitro
Corpus Striatum
nervous system diseases
Mice
Inbred C57BL
pathology [Synucleinopathies]
nervous system
Animals
Newborn
psychology [Memory Disorders]
alpha-synuclein propagation
Zdroj: Journal of Neurochemistry
Journal of neurochemistry 159(3), 554-573 (2021). doi:10.1111/jnc.15461
ISSN: 1471-4159
DOI: 10.1111/jnc.15461
Popis: 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.
Databáze: OpenAIRE
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