Endogenous Peptides in Cerebrospinal Fluid

Sammanfattning

Neurodegenerative diseases such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis involve complex biological mechanisms and remain difficult to diagnose in early stages. Since cerebrospinal fluid closely reflects changes in the central nervous system, it is considered a valuable source for discovering potential biomarkers. In this project, a mass spectrometry-based dataset of naturally occurring protein fragments in cerebrospinal fluid was analysed. Eight proteins (APP, MAPT, APLP1, CHGB, GAP43, GFAP, NEFM and CHIT1) were selected based on their relevance to neurodegeneration and fragment abundance. They were further examined regarding tissue enrichment, predominant cell type expression, subcellular localisation, and post-translational modifications. Most identified fragments originated from proteins not specifically enriched in brain tissue. However, several disease-related proteins (e.g. APP, MAPT, and CHGB) showed clear fragmentation patterns. Fragment number and length varied depending on tissue enrichment, cell type, and subcellular localisation. Secreted proteins and those predominantly expressed in oligodendrocytes generally yielded more fragments, while proteins from excitatory neurons tended to produce longer ones. Mapping of fragments and PTMs revealed that modified regions often correlated with a high density of fragmentation. Fragments of CHIT1 and GFAP were detected only in a sample from a hydrocephalus patient, suggesting possible links to neuroinflammation. In several cases, the identified fragments did not overlap with known antibody epitopes, indicating a potential limitation in traditional detection methods.Altogether, the findings show that fragment-level analysis can provide important insights into protein processing and may uncover changes not visible at the full-length protein level. This underlines the need for improved analytical techniques that can detect and characterise fragments specifically, something that could help advance biomarker development for neurodegenerative diseases.