Brainy exosomes – a novel pool for biomarker discovery in human CSF

Exosomes, endocytic vesicles ranging in size from 40–100nm, have revolutionized the field of cell–cell communication. Although they were first described in the 1980s, detailed analysis of exosome biogenesis, composition and function has occurred primarily within the past decade. The significance of exosomes is enhanced by the fact that exosomes transport packets of cellular information rather than single molecules. Exosomes contain various proteins, lipids, mRNA and miRNA packaged in discrete vesicles. As an analogy, consider the information conveyed by mailing a single letter versus sending an entire box full of letters, magazines, flyers and catalogs. The discovery of the power of exosomes allows the transmission of cellular information to be increased by this magnitude, and has also provided a new avenue for examining previously enigmatic biological processes, such as solid tumor metastasis to distant sites, diseases characterized by pathological protein inclusions such as Alzheimer’s and Creutzfeldt-Jakob disease, and the autoimmune disorder rheumatoid arthritis.

Cerebrospinal fluid (CSF) is a clear, colorless biofluid that surrounds the brain and spinal cord. It serves many purposes, including protecting the brain in the event of impact, removing waste products, and transporting signaling molecules throughout the central nervous system (CNS). Because it contains brain-derived proteins, CSF can be used for liquid biopsy to detect pathological changes that occur within the brain and spinal cord.  Biomarkers from CSF, including tau and amyloid beta peptide, have been used successfully for the diagnosis of Parkinson’s disease as well as the differentiation of this disease state from patients with Alzheimer’s disease (1).

The rich molecular content of exosomes may prove especially useful for the diagnosis of CNS disorders using CSF. Traditional biopsy is highly invasive and is not commonly used due to multiple associated risks and complications. In part because of this difficulty, there is not a single universally accepted diagnostic test for Parkinson’s or Alzheimer’s disease. Both disorders are diagnosed using a combination of neurological evaluations and tests to rule out other disorders. A recent paper by Street et al. raised the possibility that exosomes derived from CSF could provide sufficient material for disease diagnosis (2). The authors collected CSF from five patients and isolated membrane-bound vesicles using ultracentrifugation. The resulting pellet was analyzed for exosomal protein markers and examined by electron microscopy to confirm that the pellet did indeed contain exosomes. This paper provided convincing evidence that exosomes are present in CSF.

The definitive presence of exosomes in CSF provides hope for biomarker discovery. Although the paper by Street et al. was significant, the authors noted that large volumes of CSF were required for their proteomic analysis. One possible alternative is the analysis of exosomal RNA or miRNA, which would require a reduced volume of starting material. The continued search for exosomal biomarkers in CSF is guaranteed because just about anything sounds better than a brain biopsy.

Source – Qiagen