TY  - JOUR
A1  - Dauer née Joppe, Karina
A1  - Tatenhorst, Lars
A1  - Caldi Gomes, Lucas
A1  - Zhang, Shuyu
A1  - Parvaz, Mojan
A1  - Carboni, Eleonora
A1  - Roser, Anna‐Elisa
A1  - El DeBakey, Hazem
A1  - Bähr, Mathias
A1  - Vogel‐Mikuš, Katarina
A1  - Wang Ip, Chi
A1  - Becker, Stefan
A1  - Zweckstetter, Markus
A1  - Lingor, Paul
T1  - Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils
JF  - Journal of Neurochemistry
N2  - 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.
KW  - alpha‐synuclein
KW  - alpha‐synuclein propagation
KW  - alpha‐synuclein seeding
KW  - iron dyshomeostasis
KW  - Parkinson's disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262544
VL  - 159
IS  - 3
SP  - 554
EP  - 573
ER  -