Characterization of a distinct form of vimentin in the neurodegenerative brain

Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.