Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets
Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer’s disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2025-12-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-24-00865 |
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| author | Letian Huang Mingyue Liu Ze Li Bing Li Jiahe Wang Ke Zhang |
| author_facet | Letian Huang Mingyue Liu Ze Li Bing Li Jiahe Wang Ke Zhang |
| author_sort | Letian Huang |
| collection | DOAJ |
| description | Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer’s disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer’s disease. The methodological quality of the studies was assessed via the Newcastle‒Ottawa Scale. Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16–0.47, P < 0.001, I2 = 78.4%; SMD = 1.24, 95% CI: 0.01–2.48, P = 0.048, I2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35–1.66, P = 0.003, I2 = 96.5%; SMD = 7.55, 95% CI: 3.92–11.18, P < 0.001, I2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (r = 0.16, 95% CI: 0.04–0.28, P = 0.009, I2 = 74.7%), neprilysin (r = –0.47, 95% CI: –0.80–0.14, P = 0.005, I2 = 76.1%), and P-glycoprotein (r = –0.31, 95% CI: –0.51–0.11, P = 0.002, I2 = 0.0%) in patients with Alzheimer’s disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer’s disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets. |
| format | Article |
| id | doaj-art-c2e4d5ce4e1d45f49992bcaf3a02dfc3 |
| institution | Kabale University |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Wolters Kluwer Medknow Publications |
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| series | Neural Regeneration Research |
| spelling | doaj-art-c2e4d5ce4e1d45f49992bcaf3a02dfc32025-02-06T09:58:39ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582025-12-0120123574359010.4103/NRR.NRR-D-24-00865Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targetsLetian HuangMingyue LiuZe LiBing LiJiahe WangKe ZhangAmyloid-beta clearance plays a key role in the pathogenesis of Alzheimer’s disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer’s disease. The methodological quality of the studies was assessed via the Newcastle‒Ottawa Scale. Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16–0.47, P < 0.001, I2 = 78.4%; SMD = 1.24, 95% CI: 0.01–2.48, P = 0.048, I2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35–1.66, P = 0.003, I2 = 96.5%; SMD = 7.55, 95% CI: 3.92–11.18, P < 0.001, I2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (r = 0.16, 95% CI: 0.04–0.28, P = 0.009, I2 = 74.7%), neprilysin (r = –0.47, 95% CI: –0.80–0.14, P = 0.005, I2 = 76.1%), and P-glycoprotein (r = –0.31, 95% CI: –0.51–0.11, P = 0.002, I2 = 0.0%) in patients with Alzheimer’s disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer’s disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.https://journals.lww.com/10.4103/NRR.NRR-D-24-00865alzheimer’s diseaseamyloid-βblood‒brain barriercerebrospinal fluiddiagnostic biomarkermeta-analysismild cognitive impairmentperipheral bloodsystematic reviewtherapeutic targets |
| spellingShingle | Letian Huang Mingyue Liu Ze Li Bing Li Jiahe Wang Ke Zhang Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets Neural Regeneration Research alzheimer’s disease amyloid-β blood‒brain barrier cerebrospinal fluid diagnostic biomarker meta-analysis mild cognitive impairment peripheral blood systematic review therapeutic targets |
| title | Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets |
| title_full | Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets |
| title_fullStr | Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets |
| title_full_unstemmed | Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets |
| title_short | Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets |
| title_sort | systematic review of amyloid beta clearance proteins from the brain to the periphery implications for alzheimer s disease diagnosis and therapeutic targets |
| topic | alzheimer’s disease amyloid-β blood‒brain barrier cerebrospinal fluid diagnostic biomarker meta-analysis mild cognitive impairment peripheral blood systematic review therapeutic targets |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-24-00865 |
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