CROSS-DISEASE CHARACTERIZATION OF ALPHA-SYNUCLEIN PATHOLOGY IN HUMAN POSTMORTEM BRAIN TISSUE USING EPITOPE-SPECIFIC ANTIBODIES

Synucleinopathies are characterized by the presence of neuronal or glialinclusions, with a large variety of morphologies, containing the protein alpha-synuclein (aSyn). In the brain, aSyn can manifest in many different conformational and post-translationally modified variants. However, at present, little is known about the expression and localization these aSyn species in different synucleinopathies. Therefore, this study characterized the immunoreactivity of epitope-specific antibodies against aSyn’s intact C-terminus, calpain-cleaved, and phosphorylated aSyn in different brain regions of donors with Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunoreactivity was also characterized in donors with Alzheimer’s disease, progressive supranuclear palsy and age-matched non-demented controls. Revealed morphological structures were scored semi-quantitatively, and compared with the antibody KM51, used for routine diagnostics. Although all utilized antibodies detected Lewy pathology, they showed differences in morphology and the amount of immunoreactive structures. The antibody against phosphorylated aSyn revealed the largest amount and the most extensive palette of morphological structures as compared to the other antibodies in all synucleinopathies. Both the antibody against phosphorylated aSyn and the antibody against calpain-cleaved aSyn visualized substantially more glial pathology than the KM51 antibody. The antibody against the intact C-terminus of aSyn detected Lewy pathology to a lesser extent than the other antibodies, but visualized synaptic-like staining in all synucleinopathiesand non-demented controls. Hence, this antibody may detect wild-type physiological aSyn. In conclusion, epitope-specific antibodies against different aSyn species identify specific sets of morphological structures, indicating that a combination of aSyn antibodies could ameliorate the pathological diagnosis of synucleinopathies.