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Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson\u2019s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson\u2019s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson\u2019s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson\u2019s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.<\/jats:p>","DOI":"10.1093\/brain\/awab061","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T15:43:51Z","timestamp":1613663031000},"page":"1853-1868","source":"Crossref","is-referenced-by-count":118,"title":["Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9384-1279","authenticated-orcid":false,"given":"Nathalie","family":"Van Den Berge","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, 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Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcltekin","family":"Tamg\u00fcney","sequence":"additional","affiliation":[{"name":"Institute of Physical Biology, Heinrich-Heine-University, D\u00fcsseldorf, Germany"},{"name":"Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum J\u00fclich, J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e1ll","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Department of Clinical Medicine, The Danish Pain Research Center, Aarhus University, Aarhus, Denmark"},{"name":"Core Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid Juhl","family":"Terkelsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, The Danish Pain Research Center, Aarhus University, Aarhus, Denmark"},{"name":"Department of Neurology, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Randel","family":"Nyengaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Core Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"},{"name":"Center for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poul Henning","family":"Jensen","sequence":"additional","affiliation":[{"name":"DANDRITE-Danish Research Institute of Translational Neuroscience and Department of Biomedicine, Aarhus University, Aarhus, 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