Dataset Information

Human Cerebrospinal Fluid HDL-like proteome from Alzheimer Disease patients

ABSTRACT: Apolipoprotein (Apo) E4 is a key genetic risk factor for Alzheimer’s disease (AD). In the central nervous system, ApoE-containing high-density lipoprotein (HDL)-like particles transport glial cholesterol to neurons, playing a crucial role in neuronal membrane remodeling and maintenance of the myelin sheath. Despite this, the impact of HDL-like cholesterol trafficking on AD pathogenesis is not yet fully understood.The objective was to examine cholesterol transport via HDL-like particles in cerebrospinal fluid (CSF) of AD patients compared to control individuals. Additionally, we explored the ability of ApoE4-containing HDL to regulate the cholesterol efflux pathway in astrocytoma cells and facilitate cholesterol delivery to neurons.Mass spectrometry (MS) was used for a detailed analysis of the HDL-like proteome in AD patients and controls.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Alzheimer's Disease

SUBMITTER: Estefanía Núñez

LAB HEAD: Jesús Vázquez

PROVIDER: PXD057614 | Pride | 2025-09-08

REPOSITORIES: Pride

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Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer's disease and involves APOE4.

Borràs Carla C Canyelles Marina M Santos David D Rotllan Noemí N Núñez Estefanía E Vázquez Jesús J Maspoch Daniel D Cano-Sarabia Mary M Zhao Qi Q Carmona-Iragui Maria M Sirisi Sònia S Lleó Alberto A Fortea Juan J Alcolea Daniel D Blanco-Vaca Francisco F Escolà-Gil Joan Carles JC Tondo Mireia M

Journal of lipid research 20250721 8

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 ...[more]

PMID: 40701521

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Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .

			Action	DRS
	DIAN-N.zip	Other
	Gel_Carla_AD10.raw	Raw
	Gel_Carla_AD11.raw	Raw
	Gel_Carla_AD12.raw	Raw
	Gel_Carla_AD13.raw	Raw