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To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFFs) and 6\u2010hydroxydopamine (6\u2010OHDA), because aSyn PFFs induce spreading\/accumulation of aSyn, and 6\u2010OHDA rapidly causes local neuronal loss.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague\u2013Dawley rats. We investigated spread of pathological aSyn, phosphorylation of aSyn and tau, oxidative stress, synaptic\/neuronal loss and cognitive dysfunction 60, 90 and 120\u2009days after injection. Similarly, we injected 6\u2010OHDA into the MFB and examined the same parameters 1 and 3\u00a0weeks after injection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Following aSyn PFF injection, phosphorylated aSyn was found distant from the injection site in the hippocampus and frontal cortex. However, despite neuron loss being evident close to the site of injection in the substantia nigra at 120\u2009days post injection, there were no other neurodegeneration\u2010associated features associated with aSyn including synaptic loss. In contrast, 6\u2010OHDA caused severe neuronal loss in the substantia nigra at 3\u2009weeks post injection that was accompanied by phosphorylation of aSyn and tau, oxidative stress, loss of synaptic proteins, cognitive and motor dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that spread\/replication and slow accumulation of pathological aSyn may not be sufficient to induce neurodegenerative changes. In contrast, oxidative stress responses in addition to aSyn accumulation were associated with other Parkinson's disease (PD)\u2010associated abnormalities and cognitive dysfunction. Our results may be important when considering why only some PD patients develop dementia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12829","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T16:50:16Z","timestamp":1655830216000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Investigating key factors underlying neurodegeneration linked to alpha\u2010synuclein spread"],"prefix":"10.1111","volume":"48","author":[{"given":"Cindy C. C.","family":"Pang","sequence":"first","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"},{"name":"Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja H.","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krit","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelvin C.","family":"Luk","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John Q.","family":"Trojanowski","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia M. Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7898-4295","authenticated-orcid":false,"given":"Wendy","family":"Noble","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-7993","authenticated-orcid":false,"given":"Raymond C. 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