Investigation of the choroid plexus implication in Alzheimer’s disease pathophysiology using human proteomics and mouse transcriptomics

Abstract

AbstractBackgroundThe choroid plexus (CP) is responsible for the production of cerebrospinal fluid (CSF), transport of proteins to the CSF and clearance of proteins from the CSF. The CP becomes compromised during aging, which is exacerbated in AD. Nonetheless, the relation between CP and AD pathophysiology remains unclear. We aim to investigate the pathophysiology underlying the CP involvement in AD, utilizing human CSF proteomics and mouse CP transcriptomics.MethodWe included 526 individuals from EMIF‐AD MBD, St Louis Knight ADRC and Maastricht BB‐ACL studies. Based on CSF Aβ1‐42 (A, data‐driven cut‐offs), individuals were classified as controls (cognitively normal (CN) A‐, n = 171) or as amyloid‐positive (CN A+, n = 120; mild cognitive impairment (MCI) A+, n = 154; AD A+, n = 81). CSF proteomic data were generated using TMT spectrometry and protein concentrations were compared using ANOVA adjusted for age and sex. Transcriptomic was performed in CP tissue of APPNL‐G‐F (n = 17) and wild‐type C57BL/6J (n = 17) mice using Illumina RNA‐Seq and differential expression analysis was conducted. Next, Gene Ontology and Ingenuity Pathway analyses were performed. For proteomics, high expression of proteins in the CP was identified based on Allen Brain Atlas and the R package ABAEnrichment.ResultIn CN A+, 51 proteins were increased and 21 decreased relative to controls. Out of those increased proteins, 57% were enriched for expression in the CP (ABAEnrichment P<0.001, Figure 1) and were associated with lysosomes and the CLEAR pathway, extracellular matrix and coagulation. A similar pattern was observed for both MCI A+ and AD A+ compared to controls, with a significant percentage of increased proteins enriched for expression in the CP (22 to 30%), which are related to lysosomes and the CLEAR pathway, extracellular matrix and coagulation. In APPNL‐G‐F compared to wild‐type mice, CP transcriptomics revealed 313 upregulated and 198 downregulated genes (Figure 2). The upregulated genes were also associated with the lysosomes and the CLEAR pathway, as well as energy metabolism and lipids.ConclusionHuman proteomics and mice transcriptomics studies suggest an association between amyloid pathology, CP functioning and lysosomes. Dysfunction of lysosomes in AD could relate to compromised clearing events. This is important for future research and AD treatment development.