Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4
Por:
Borràs, C, Canyelles, M, Santos, D, Rotllan, N, Núñez, E, Vàzquez, J, Maspoch, D, Cano-Sarabia, M, Zhao, Q, Carmona-Iragui, M, Sirisi, S, Lleó, A, Fortea, J, Alcolea, D, Blanco-Vaca, F, Escolà-Gil, JC, Tondo, M
Publicada:
1 ago 2025
Ahead of Print:
1 ago 2025
Resumen:
In the central nervous system, apolipoprotein (APO)E-containing lipoprotein particles mediate the transport of glial-derived cholesterol to neurons, which is essential for neuronal membrane remodeling and maintenance of the myelin sheath. We aimed to examine cholesterol transport via lipoprotein particles in cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients compared to control individuals. Additionally, we explored the ability of reconstituted HDL containing different APOE isoforms to regulate cholesterol transport. We evaluated the capacity of CSF lipoprotein particles to facilitate radiolabeled unesterified cholesterol efflux from A172 human glioblastoma astrocytes and to deliver cholesterol to SH-SY5Y human neuronal cells. The CSF lipoprotein proteome was analyzed by LC-MS/MS. Reconstituted HDL nanoparticles were prepared by combining phospholipids and cholesterol with human APOE3 or APOE4, followed by radiolabeling with unesterified cholesterol. Our results showed that cholesterol efflux from astrocytes to CSF were similar between AD patients and controls, both under baseline conditions and after activation of ABCA1 and ABCG1. However, CSF lipoprotein-mediated neuronal cholesterol uptake was significantly reduced in the AD group. LC-MS/ MS analysis identified 239 proteins associated with CSF lipoproteins in both groups, with no major alterations in proteins linked to cholesterol metabolism. However, 27 proteins involved in noncholesterol-related processes were differentially expressed. Notably, synthetic reconstituted HDL particles containing APOE4 exhibited reduced capacity to deliver cholesterol to neurons compared to those with APOE3. These findings indicate that CSF lipoproteins from patients with AD demonstrate impaired cholesterol delivery to neurons. Our study highlights APOE4 as a critical contributor to abnormal neuronal cholesterol uptake in AD pathophysiology.
Filiaciones:
Borràs, C:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Canyelles, M:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Santos, D:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Rotllan, N:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Núñez, E:
Ctr Nacl Invest Cardiovasc Carlos III, Madrid, Spain
CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain
Vàzquez, J:
Ctr Nacl Invest Cardiovasc Carlos III, Madrid, Spain
CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain
Maspoch, D:
CSIC, Catalan Inst Nanosci & Nanotechnol ICN2, Barcelona, Spain
Barcelona Inst Sci & Technol, Barcelona, Spain
Univ Autonoma Barcelona UAB, Dept Quim, Fac Ciencies, Barcelona, Spain
ICREA Inst Catalana Invest & Estudis Avancats, Barcelona, Spain
Cano-Sarabia, M:
CSIC, Catalan Inst Nanosci & Nanotechnol ICN2, Barcelona, Spain
Barcelona Inst Sci & Technol, Barcelona, Spain
Univ Autonoma Barcelona UAB, Dept Quim, Fac Ciencies, Barcelona, Spain
Zhao, Q:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
Carmona-Iragui, M:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
CIBERNED, CIBER Enfermedades Neurodegenerat, Madrid, Spain
Sirisi, S:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
CIBERNED, CIBER Enfermedades Neurodegenerat, Madrid, Spain
Lleó, A:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
CIBERNED, CIBER Enfermedades Neurodegenerat, Madrid, Spain
Fortea, J:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
CIBERNED, CIBER Enfermedades Neurodegenerat, Madrid, Spain
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Alcolea, D:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
CIBERNED, CIBER Enfermedades Neurodegenerat, Madrid, Spain
Blanco-Vaca, F:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Escolà-Gil, JC:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Tondo, M:
Inst Recerca St Pau IR St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Biochem, Barcelona, Spain
Green Submitted, Green Accepted, gold
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