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. 2024 May 31;10(22):eadl1123.
doi: 10.1126/sciadv.adl1123. Epub 2024 May 29.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model

Pu-Yang Sun  1   2 , Jie Liu  1   2 , Jian-Ni Hu  1   2 , Yun-Feng Tu  1   2 , Qiu Jiang  1   2 , Yu-Juan Jia  1   2 , Hao-Lun Sun  1   2   3 , Si-Han Chen  1   2   4 , Jia-Yan Xin  1   2 , Zhong-Yuan Yu  1   2 , Zhi-Hao Liu  1   2 , Cheng-Rong Tan  1   2 , Gui-Hua Zeng  1   2 , An-Yu Shi  1   2 , Yu-Hui Liu  1   2   5 , Xian-Le Bu  1   2   5 , Yan-Jiang Wang  1   2   5   6   7 , Jun Wang  1   2
Affiliations

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model

Pu-Yang Sun et al. Sci Adv. .

Abstract

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

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Figures

Fig. 1.
Fig. 1.. Construction of a PBMC single-cell transcriptomic atlas.
(A) Schematic diagram of the establishment of the BMT mouse model. (B) t-Distributed stochastic neighbor embedding (t-SNE) projection of 45,711 cells from PBMCs in the control YTg (n = 4), control OTg (n = 4), and YTg BMC groups (n = 4). A total of nine cell types, including B cells (clusters 1 to 6), CD4+ T cells (clusters 7, 11, and 12), CD8+ T cells (clusters 8 to 10), monocytes (clusters 13 and 14), macrophages (cluster 15), natural killer (NK) cells (cluster 16), basophils (cluster 17), neutrophils (cluster 18), and dendritic cells (cluster 19), were characterized. (C) Canonical cell type–specific markers define B cells, CD4+ T cells, CD8+ T cells, monocytes, basophils, neutrophils, NK cells, and macrophages. (D) Heatmap of the top 10 marker genes from each cell type. The color key indicates the fold change level. (E) Proportions of the main immune cell types in control YTg, control OTg, and YTg BMC mice. These proportions were calculated by dividing the number of cells of each type by the total number of cells in each sample from the processed single-cell sequencing data.
Fig. 2.
Fig. 2.. Young BMT restored the expression of aging DEGs in multiple cell types of PBMCs.
(A) Scatter plot of the general aging differentially expressed genes (DEGs; cutoff by P < 0.05, log2FC > 0.5) in PBMCs. (B) The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms enriched by the general aging and reverse DEGs. Red: up-regulated pathways; blue: down-regulated pathways. (C) Pie plots of the aging DEGs in monocytes, CD8+ T cells, CD4+ T cells, B cells, and NK cells. (D) Heatmap of the reversed DEGs in each cell type alongside the young BMT. The color key indicates the log2FC values. (E) The expression of differentially expressed AD risk genes in aging and BMT of B cells, CD4+ T cells, CD8+ T cells, NK cells, and monocytes. The color indicates the log2FC values. (F) Venn plot of the identified transcription factors (TFs) and aging DEGs in PBMCs. (G) Heatmap of the expression level of TFs in each cell type. The color key indicates the log2FC values. (H) Dot plots of the effects of aging and young BMT on TFs expression. The color key indicates the log2FC values. (I) Bar plots of the GO terms enriched by the target genes of Nfe2, Cepbp, and Nr1h3. The downstream genes of Nfe2, Cepbp, and Nr1h3 were obtained from the regulon analysis using SCENIC, and the genes identified through SCENIC analysis may not be DEGs. *P < 0.05; **P < 0.01; ***P < 0.001. The error bars are the SEMs. NES(ABS), absolute normalized enrichment score; FC, fold change.
Fig. 3.
Fig. 3.. Young BMT rescued the impaired Aβ phagocytosis capacity of blood monocytes.
(A) Levels of expression of the Aβ uptake-related receptors Tlr2, Cd33, Msr1, and Syk. One-way analysis of variance (ANOVA). (B) In vitro analysis of Aβ42 phagocytosis by monocytes with flow cytometry. (C and D) Quantification of the levels of monocyte Aβ42 uptake. One-way ANOVA. (E) Bar plots of the number and strength of cell interactions in control YTg, control OTg, and YTg BMC mice. (F) Scatter plots of cell interaction strength in control YTg, control OTg, and YTg BMC mice. (G) Cell-to-cell interaction network between monocytes and the rest of the cell types. *P < 0.05; **P < 0.01; ***P < 0.001. The error bars are the SEMs.
Fig. 4.
Fig. 4.. Young BMT reduced Aβ levels in APP/PS1 mice.
(A and B) Immunostaining and quantification of Aβ plaques stained with 6E10 (total plaques) and Congo red (dense plaques) in the neocortices and hippocampus of APP/PS1 mice with or without BMT. One-way ANOVA. (C) Comparison of Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratios in the tris-buffered saline (TBS; soluble extracellular Aβ), SDS (intracellular Aβ), and FA (dense plaques Aβ) fractions of brain homogenates among BMT and control mice. One-way ANOVA. (D) Comparison of Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratio in plasma among BMT and control mice. One-way ANOVA. n = 8 per group. *P < 0.05; **P < 0.01; ***P < 0.001. The scale bar is 500 μm. The error bars are the SEMs. FA, formic acid.
Fig. 5.
Fig. 5.. Young BMT alleviated AD-related pathogenesis.
(A and B) Immunostaining and quantification of microglia stained with CD68 in the neocortex and hippocampus of APP/PS1 mice with or without BMT. One-way ANOVA. (C) Statistical analysis of the levels of inflammatory factors, including interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), and interleukin-10 (IL-10), in brain homogenate. One-way ANOVA. (D to G) Representative images and quantification of neurons (NeuN, red) and dendrites (MAP2, green) in the hippocampal CA1 region and neural apoptosis (caspase-3, green) in the hippocampal CA3 region. One-way ANOVA. (H) Volumes of the hippocampus, lateral ventricle, and neocortex. One-way ANOVA. n = 8 per group; *P < 0.05; **P < 0.01; ***P < 0.001. The scale bar in (A) is 500 μm, and the scale bars in (D) and (F) are 20 μm. The error bars are the SEMs.
Fig. 6.
Fig. 6.. Young BMT rescued the cognitive impairment of APP/PS1 mice.
(A) Schematic presentation of the experimental design used to investigate the effect of young BMT on cognition in APP/PS1 mice. (B and C) Representative images of the open-field test and statistics of the number of rearing events, average speed, and time spent in the center. One-way ANOVA. (D and E) Representative images of the spontaneous alteration test and statistics of the ratio of alternations. One-way ANOVA. (F and G) Representative images of the new arm test and statistics of the ratio of time and times entering the new arm. One-way ANOVA. n = 8 per group; *P < 0.05; **P < 0.01; ***P < 0.001. The error bars are the SEMs.
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