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

• DOI: 10.1111/jnc.15461
• Publication Date: 2021-06-27T19:05:18Z
• Authors: Karina Dauer née ...; Lars Tatenhorst; Lucas Caldi Gomes; Shuyu Zhang; Mojan Parvaz; Eleonora Carboni; Anna‐Elisa Roser; Hazem El DeBakey; Mathias Bähr; Katarina Vogel‐Mikuš; Chi Wang Ip; Stefan Becker; Markus Zweckstetter; Paul Lingor
• Keywords: administration & dosage [Iron]; Male; Microinjections; Synucleinopathies; Parkinson's disease; alpha-synuclein; Iron; administration & dosage [alpha-Synuclein]; Motor Activity; toxicity [alpha-Synuclein]; Mice; 03 medical and health sciences; Connectome; Animals; Humans; ddc:610; metabolism [alpha-Synuclein]; metabolism [Synucleinopathies]; Brain Chemistry; ddc:610; Memory Disorders; 0303 health sciences; Dose-Response Relationship, Drug; drug effects [Motor Activity]; pathology [Microglia]; chemically induced [Memory Disorders]; alpha-synuclein seeding; iron dyshomeostasis; pharmacology [Iron]; Corpus Striatum; Mice, Inbred C57BL; pathology [Synucleinopathies]; Animals, Newborn; psychology [Memory Disorders]; alpha-Synuclein; Female; alpha-synuclein propagation; Microglia

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 is known to bind α-syn, facilitating its aggregation regulating α-syn expression, it remains unclear if how also modulates spreading. To elucidate influence of on propagation pathology, we investigated after stereotactic injection preformed fibrils (PFFs) into striatum mouse brains neonatal brain enrichment. C57Bl/6J pups received oral gavage with 60, 120, or 240 mg/kg carbonyl vehicle between postnatal days 10 17. At 12 weeks age, intrastriatal injections 5-µg PFFs were performed induce seeding aggregates. 90 post-injection, PFFs-injected mice displayed long-term memory deficits, without affection motor behavior. Interestingly, quantification phosphorylated at S129 showed reduced attenuated connectome-specific regions Furthermore, caused microglia accumulation, which was alleviated by a dose-dependent way. In primary cortical neurons microfluidic chamber model vitro, application did not alter trans-synaptic propagation, possibly indicating an involvement non-neuronal cells this process. Our study suggests that may cognitive deficits independent iron. However, redistribution aggregate reduction striatal be mediated via iron-induced alterations connectome.