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Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats
Brain. 2021 Jul 28;144(6):1853-1868. doi: 10.1093/brain/awab061.
Nathalie Van Den Berge 1 2, Nelson Ferreira 3 4, Trine Werenberg Mikkelsen 1, Aage Kristian Olsen Alstrup 1 2, Gültekin Tamgüney 5 6, Páll Karlsson 1 7 8, Astrid Juhl Terkelsen 7 9, Jens Randel Nyengaard 1 8 10, Poul Henning Jensen 3 4, Per Borghammer 1 2
Abstract:
...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's 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's 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's 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.
PMID: 33880502
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320301/
Tags: alpha-synuclein, gut, nerves, parkinson's, rats