TY - JOUR
T1 - Axonal degeneration in the anterior insular cortex is associated with Alzheimer's co-pathology in Parkinson's disease and dementia with Lewy bodies
AU - Fathy, Yasmine Y
AU - Jonkman, Laura E
AU - Bol, John J
AU - Timmermans, Evelien
AU - Jonker, Allert J
AU - Rozemuller, Annemieke J M
AU - van de Berg, Wilma D J
N1 - Funding Information: This work was funded by a grant from the Stichting ParkinsonFonds, SPF 38000, project number: 105475. Funding Information: We are grateful to all individuals that donated their brains to the Netherlands Brain Bank (NBB; www.brainbank.nl), without their precious donations, this work would not have been possible. We thank the team of the NBB, in particular Michiel Kooreman, for their cooperation and their help in the collection of brain tissue. The authors would like to thank John Breve for his help testing western blot, Joost Heuvelink for technical assistance, and Jos Twisk for statistical advice. We also thank Marko Popovic and the Advanced Optical Microscopy Core O|2 (www.ao2m.amsterdam) for support with confocal imaging. We also thank Dr. Wagner Zago (Prothena Biosciences Inc, USA) for kindly providing the 11A5 pSer129-aSyn antibody and Dr. Markus Britschgi and Daniel Mona (Roche, Basel, Switzerland) for labelling the aSyn antibody with fluorochromes for multilabel 3D confocal laser scannning microscopic analysis of human brain tissue samples. This research was supported by Stichting Parkinson Fonds, Netherlands. Funding Information: Dr. Wilma van de Berg was financially supported in period 2019–2021 by grants from Amsterdam Neuroscience, Dutch Research council (ZonMW 70–73305-98–106; 70–73305-98–102; 40–46000-98–101), Stichting Parkinson Fonds (Insula 2014), MJ Fox foundation (17253) and Parkinson Association (2020-G01). Dr. Wilma van de Berg performed contract research and consultancy for Hoffmann-La Roche, Roche Tissue Diagnostics, Crossbeta Sciences and received research consumables from Hoffmann-La Roche and Prothena. All authors declare no conflict of interest. Funding Information: We are grateful to all individuals that donated their brains to the Netherlands Brain Bank (NBB; www.brainbank.nl ), without their precious donations, this work would not have been possible. We thank the team of the NBB, in particular Michiel Kooreman, for their cooperation and their help in the collection of brain tissue. The authors would like to thank John Breve for his help testing western blot, Joost Heuvelink for technical assistance, and Jos Twisk for statistical advice. We also thank Marko Popovic and the Advanced Optical Microscopy Core O|2 ( www.ao2m.amsterdam ) for support with confocal imaging. We also thank Dr. Wagner Zago (Prothena Biosciences Inc, USA) for kindly providing the 11A5 pSer129-aSyn antibody and Dr. Markus Britschgi and Daniel Mona (Roche, Basel, Switzerland) for labelling the aSyn antibody with fluorochromes for multilabel 3D confocal laser scannning microscopic analysis of human brain tissue samples. This research was supported by Stichting Parkinson Fonds, Netherlands. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/7
Y1 - 2022/12/7
N2 - BACKGROUND: Axons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB.METHODS: α-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.RESULTS: Compared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit.CONCLUSIONS: Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.
AB - BACKGROUND: Axons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB.METHODS: α-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.RESULTS: Compared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit.CONCLUSIONS: Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.
KW - Alzheimer’s disease pathology
KW - Axonal length density
KW - Insular subregions
KW - Myelin
KW - Neurofilament
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=85143498099&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s40035-022-00325-x
DO - https://doi.org/10.1186/s40035-022-00325-x
M3 - Article
C2 - 36474289
SN - 2047-9158
VL - 11
SP - 52
JO - Translational Neurodegeneration
JF - Translational Neurodegeneration
IS - 1
M1 - 52
ER -