Proteomics analyses of CSF and Plasma for discovery of early vascular pathologies in neurodegenerative disease
Year: 2023
Type: article
Study design: Observational Study
Abstract: Background Cerebral small vessel disease (cSVD) is a major cause of brain degeneration and dementia for which we have no therapies. My lab applies new molecular omics technology to human biospecimen for an initial unbiased approach to discovery of clinically‐relevant dysregulated molecular pathways in humans living with disease. To this end, we have focused our efforts on an autosomal dominant form of disease–CADASIL (Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy) caused by mutations in NOTCH3 . Given its autosomal dominant nature, CADASIL provides a unique opportunity to build an all‐in‐human modeling pipeline for therapeutic discovery. Method We have performed proteomics analyses in plasma samples (CADASIL n = 58, controls n = 60) as an unbiased starting point for discovery of dysregulated molecular pathways and are building patient iPSC derived multi‐cellular in vitro models (iCADASIL) to identify molecular drivers of pathological cell‐cell communications within the neuro‐glio‐vascular unit. Both bulk proteomics as well as spatial transcriptomics (GeoMx, Nanostring) from donated brain samples are used to extract disease‐associated molecular signatures from human tissue for (1) testing the validity of iCADASIL models, and for (2) comparison with blood proteomics and identification of promising plasma biomarkers for non‐invasive staging of neurovascular pathology in living humans for the purposes of future clinical trial design. Result Our initial results indicate that dysregulations in angiogenesis, changes to extracellular matrix and immune dysfunction, including neutrophilic activation, may be features of early disease stages with relevance to mild brain phenotypes such as slowed processing speed and executive dysfunction. In vitro angiogenesis assays and immune cell extravasation assays are underway in our iCADASIL models. Conclusion The unbiased proteomics performed on CADASIL ‐ control plasma confirmed known molecular dysregulations as well as identified new avenues of investigation that we are pursuing via iCADASIL models. The combination of omics methods applied to multiple biospecimen, including in vivo plasma and ex vivo brain tissue provides a powerful approach for discovery of therapeutically targetable pathways with relevance to disease‐associated phenotypes.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.073997
Author: Fanny M Elahi
Institution: Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390199292