Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies

Fluids Barriers CNS. 2024 Jul 18;21(1):58. doi: 10.1186/s12987-024-00555-3.

ABSTRACT

BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.

METHODS: We used an APP knock-in mouse model, APP^NL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD.

RESULTS: ChP tissue proteome was dysregulated in APP^NL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways.

CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

PMID:39020361 | PMC:PMC11256635 | DOI:10.1186/s12987-024-00555-3