Bisdemethoxycurcumin (BDC)-Loaded H-Ferritin-Nanocages Mediate the Regulation of Inflammation in Alzheimer’s Disease Patients

Abstract

Background: Bisdemethoxycurcumin (BDC) might be an inflammation inhibitor in Alzheimer’s Disease (AD). However, BDC is almost insoluble in water, poorly absorbed by the organism, and degrades rapidly. We thus developed a new nanoformulation of BDC based on H-Ferritin nanocages (BDC-HFn). Methods: We tested the BDC-HFn solubility, stability, and ability to cross a blood–brain barrier (BBB) model. We tested the effect of BDC-HFn on AD and control (CTR) PBMCs to evaluate the transcriptomic profile by RNA-seq. Results: We developed a nanoformulation with a diameter of 12 nm to improve the solubility and stability. The comparison of the transcriptomics analyses between AD patients before and after BDC-HFn treatment showed a major number of DEG (2517). The pathway analysis showed that chemokines and macrophages activation differed between AD patients and controls after BDC-HFn treatment. BDC-HFn binds endothelial cells from the cerebral cortex and crosses through a BBB in vitro model. Conclusions: Our data showed how BDC-Hfn could improve the stability of BDC. Significant differences in genes associated with inflammation between the same patients before and after BDC-Hfn treatment have been found. Inflammatory genes that are upregulated between AD and CTR after BDC-HFn treatment are converted and downregulated, suggesting a possible therapeutic approach.

Computational analysis of peripheral blood RNA sequencing data unravels disrupted immune patterns in Alzheimer's disease

“…The network produced by the STRING tool comprised 22 out of the 49 DEGs, with 44 edges between them, while the MCL clustering algorithm revealed 4 distinct protein clusters related to immune responses (HLA-A, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-E, MICB, PPP1R11, PSMB9, SPOPL, TRIM26), the cellular response to UVA and interleykin-1 and chitin catabolic process (CCL18, CHI3L1, CHIT1, MMP2, MMP9, OLR1), the hydrogen peroxide catabolic process, and nitric oxide (NO) and carbon dioxide transportation (HBA2, HBB, RPS9), as highlighted in Figure 1 . This evidence is previously supported [11] . It has been stressed that the accumulation of chitin in the body may play a significant role in AD, potentially triggering cognitive decline due to its neurotoxic properties and subsequent induction of neuroinflammation [24] , [25] .…”

“…Our analysis was applied to the peripheral blood mononuclear cells (PBMCs) generated by Gagliardi et al [11] (GEO accession number: GSE203408). This dataset contains RNA-seq data that was derived from AD patients and healthy controls.…”

Ferritin-based nanomedicine for disease treatment

“…Cyclosporine A-loaded ferritin crossed BBB efficiently and showed a significant therapeutic effect on cerebral ischemia/reperfusion injury in mice [ 41 ]. Bisdemethoxycurcumin-loaded ferritin penetrated BBB model and showed potential to regulate inflammation in Alzheimer’s disease [ 178 ]. Ferritin carrying ATP inside could cross blood-testis barrier (BTB) and accumulate in the sperm heads, improving sperm motility and facilitating ATP-dependent asthenozoospermia treatment [ 52 ].…”

Crocin ameliorates neuroinflammation and cognitive impairment in mice with Alzheimer's disease by activating PI3K/AKT pathway

“…Inflammation also plays a fundamental role in AD. Studies have shown that patients with AD have elevated levels of inflammatory markers (Gagliardi et al., 2022 ). Additionally, inhibiting inflammation in AD has been found to slow cognitive decline (Nillert et al., 2022 ).…”