Investigating key factors underlying neurodegeneration linked to alpha‐synuclein spread
Aims It has long been considered that accumulation of pathological alpha‐synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFFs) and 6‐hydroxydopamine...
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Published in | Neuropathology and applied neurobiology Vol. 48; no. 6; pp. e12829 - n/a |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Wiley Subscription Services, Inc
01.10.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Aims
It has long been considered that accumulation of pathological alpha‐synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFFs) and 6‐hydroxydopamine (6‐OHDA), because aSyn PFFs induce spreading/accumulation of aSyn, and 6‐OHDA rapidly causes local neuronal loss.
Methods
We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague–Dawley rats. We investigated spread of pathological aSyn, phosphorylation of aSyn and tau, oxidative stress, synaptic/neuronal loss and cognitive dysfunction 60, 90 and 120 days after injection. Similarly, we injected 6‐OHDA into the MFB and examined the same parameters 1 and 3 weeks after injection.
Results
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 days post injection, there were no other neurodegeneration‐associated features associated with aSyn including synaptic loss. In contrast, 6‐OHDA caused severe neuronal loss in the substantia nigra at 3 weeks post injection that was accompanied by phosphorylation of aSyn and tau, oxidative stress, loss of synaptic proteins, cognitive and motor dysfunction.
Conclusions
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)‐associated abnormalities and cognitive dysfunction. Our results may be important when considering why only some PD patients develop dementia. |
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Bibliography: | Funding information The study is supported by Innovative and Technology Fund (ITS/381/15) from Innovative and Technology Commission, Seed Funding for Basic Science Research (201910159221 and 201711159222) from The University of Hong Kong. CCCP and MHS are fully supported by Postgraduate Stipend from the Graduate School, LKS Faculty of Medicine and research fund from RCCC, The University of Hong Kong. CCCP is also supported by research funds from WN, King's College London, and the King's College London Alzheimer's Research UK Network Centre. JQT and VMYL were supported in this study in part by grants from the National Institutes of Health (AG10124, AG16573, AG17586, R01AG021055, R01AG042444, P50AG16573 and MH64045). National Institutes of Health, Grant/Award Numbers: MH64045, P50AG16573, R01AG042444, R01AG021055, AG17586, AG16573, AG10124; Seed Funding for Basic Science Research, Grant/Award Numbers: 201711159222, 201910159221; King's College London Alzheimer's Research UK Network Centre; King's College London; The University of Hong Kong; Graduate School, LKS Faculty of Medicine; Innovative and Technology Fund, Grant/Award Number: ITS/381/15 In memoriam. We dedicate this manuscript to the memory of Professor John Trojanowski as he passed away while the manuscript was being reviewed. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0305-1846 1365-2990 |
DOI: | 10.1111/nan.12829 |