Proteomic alterations in the brain and blood–brain barrier during brain Aβ accumulation in an APP knock-in mouse model of Alzheimer’s disease

Fluids and Barriers of the CNS

Research

Takashi Saito¹  Sumio Ohtsuki²  Takeshi Masuda²  Shingo Ito²  Ryotaro Yagi³  Seiryo Ogata⁴  Takaomi Saido⁵ 

[1] Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467–8601, Nagoya, Japan;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2–1 Hirosawa, Wako, 351–0198, Saitama, Japan;Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5–1 Oe-honmachi, Chuo-ku, 862–0973, Kumamoto, Japan;Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5–1 Oe-honmachi, Chuo-ku, 862–0973, Kumamoto, Japan;Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5–1 Oe-honmachi, Chuo-ku, 862–0973, Kumamoto, Japan;Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5–1 Oe-honmachi, Chuo-ku, 862–0973, Kumamoto, Japan;Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2–1 Seiryo-machi, Aoba-ku, 980–8575, Sendai, Japan;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2–1 Hirosawa, Wako, 351–0198, Saitama, Japan;

关键词: Alzheimer’s disease;    Amyloid-β peptide;    Blood–brain barrier;    Apolipoprotein;    Basement membrane;    Proteome analysis;   

DOI  :  10.1186/s12987-023-00466-9

 received in 2023-04-04, accepted in 2023-09-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundBlood–brain barrier (BBB) dysfunction is supposed to be an early event in the development of Alzheimer’s disease (AD). This study aimed to investigate the relationship between BBB alterations and AD progression in terms of amyloid-β peptide (Aβ) accumulation in the brains of humanized amyloid precursor protein knock-in (APP-KI) mice.MethodsBrain Aβ accumulation was examined using immunohistochemical analysis. Alterations in differentially expressed proteins were determined using sequential window acquisition of all theoretical fragment ion mass spectroscopy (SWATH-MS)-based quantitative proteomics, and Metascape, STRING, Gene Ontology, and KEGG were used for network analyses of altered biological pathways and processes. Statistical significance was determined using the unpaired two-tailed Student’s t-test and Welch’s t-test for two groups and one-way analysis of variance followed by Tukey’s test for more than two groups. Correlations between two groups were determined using Pearson’s correlation analysis.ResultsBrain Aβ accumulation in APP-KI mice was detectable at 2 months, increased significantly at 5 months, and remained elevated at 12 months of age. The levels of differentially expressed proteins in isolated brain capillaries were higher in younger mice, whereas those in the brain were higher in older mice. Network analyses indicated changes in basement membrane-associated and ribosomal proteins in the brain capillaries. There were no significant changes in key proteins involved in drug or Aβ transport at the BBB. In contrast, solute carrier transporter levels in astrocytes, microglia, and neurons were altered in the brain of older mice. Moreover, the levels of the lipid transporters Apoe and Apoj were upregulated in both the brain and isolated brain capillaries after Aβ accumulation.ConclusionsOur results suggest that changes in the brain occurred after advanced Aβ accumulation, whereas initial Aβ accumulation was sufficient to cause alterations in the BBB. These findings may help elucidate the role of BBB alterations in AD progression and predict the distribution of drugs across the BBB in the brain of patients with AD.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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