Modulation of inflammatory regulation by plasma exchange with albumin replacement revealed by deep plasma and CSF proteomic profiling of the AMBAR study
Year: 2023
Type: article
Abstract: Background AMBAR trial (phase 2b/3 clinical trial) evaluates plasma exchange efficacy with albumin replacement (PE‐Alb) in mild‐to‐moderate Alzheimer’s Disease (AD) patients. It includes an intensive period (IP) comprising 6‐weeks of conventional therapeutic PE‐Alb (TPE; 1 TPE/week) followed by 12‐month maintenance period of low volume PE‐Alb (LVPE; 1 LVPE/month). Our previous study reporting deep plasma and CSF proteomics profiling identified multiple AD‐associated pathways modulated by PE‐Alb (Feng et al. CTAD2022). Here we dissected immune pathways changes over time and reported their crosstalk between plasma and CSF to further understand molecular mechanisms of PE‐Alb. Method 7288 proteins were measured by SomaScan technology in 671 plasma samples (148 patients, 5 visits) and 422 CSF samples (144 patients, 3 visits). Acute effects (post‐TPE/LVPE versus pre‐TPE/LVPE samples) for plasma, and lasting effects (baseline to either end of IP or end of study (EOS)) for both matrices were calculated through a mixed model approach comparing PE‐Alb‐treated patients versus placebo. Network features of the top identified proteoforms were explored in STRING and OmniPath databases. Relationships between enriched pathways were analyzed by pathway crosstalk based on Jaccard coefficient and correlations between plasma and CSF proteomes at each visit were calculated by spearman correlation. Result Plasma samples showed that 90 proteoforms from acute TPE, 16 from acute LVPE, and 14 at the end of IP were significantly decreased and enriched in immune and inflammation‐related pathways. Three proteins involved in immunoglobulin‐mediated immune pathways were in the core of the interactome network and were consistently decreasing over time, one of them also significantly decreased in the CSF proteome. Finally, 113 proteins with spearman correlations >0.5 at least at one of the 3 visits were detected and were significantly enriched in immune system functions (adjusted‐pvalue<0.05). Conclusion This analysis demonstrates acute and lasting PE‐Alb effects on immune and inflammatory pathways. We identified 3 potential players and a crosstalk between plasma and CSF immune proteomes, suggesting the importance of the modulation of peripheral inflammation in AD treatment. This study further helps understand the molecular basis of AMBAR therapeutic approach that may contribute to slowing down AD progression.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.079113
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390192894