TY - JOUR
T1 - Involvement of the choroid plexus in Alzheimer's disease pathophysiology
T2 - findings from mouse and human proteomic studies
AU - Delvenne, Aurore
AU - Vandendriessche, Charysse
AU - Gobom, Johan
AU - Burgelman, Marlies
AU - Dujardin, Pieter
AU - De Nolf, Clint
AU - Tijms, Betty M.
AU - Teunissen, Charlotte E.
AU - Schindler, Suzanne E.
AU - Verhey, Frans
AU - Ramakers, Inez
AU - Martinez-Lage, Pablo
AU - Tainta, Mikel
AU - Vandenberghe, Rik
AU - Schaeverbeke, Jolien
AU - Engelborghs, Sebastiaan
AU - De Roeck, Ellen
AU - Popp, Julius
AU - Peyratout, Gwendoline
AU - Tsolaki, Magda
AU - Freund-Levi, Yvonne
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Bertram, Lars
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Visser, Pieter Jelle
AU - Vandenbroucke, Roosmarijn E.
AU - Vos, Stephanie J. B.
PY - 2024/7/18
Y1 - 2024/7/18
N2 - BackgroundStructural 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.MethodsWe used an APP knock-in mouse model, APPNL-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.ResultsChP tissue proteome was dysregulated in APPNL-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.ConclusionsTogether, 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.
AB - BackgroundStructural 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.MethodsWe used an APP knock-in mouse model, APPNL-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.ResultsChP tissue proteome was dysregulated in APPNL-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.ConclusionsTogether, 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.
KW - Alzheimer's disease
KW - Choroid plexus
KW - Cerebrospinal fluid
KW - Proteomics
KW - APP knock-in mice
KW - Amyloid-beta (A beta)
KW - CEREBROSPINAL-FLUID PRODUCTION
KW - MODEL
KW - EXPRESSION
KW - TRANSPORT
KW - VESSELS
KW - BARRIER
KW - ADULT
U2 - 10.1186/s12987-024-00555-3
DO - 10.1186/s12987-024-00555-3
M3 - Article
SN - 2045-8118
VL - 21
JO - Fluids and barriers of the CNS
JF - Fluids and barriers of the CNS
IS - 1
M1 - 58
ER -