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Young bone marrows transplantation rejuvenates immune cells, attenuate cerebral Aβ accumulation and related pathologies in Alzheimer’s disease model mouse

ABSTRACT: Immunesenescence contributes to systematic aging and participates in the pathogenesis of Alzheimer’s disease (AD). To define the potential of immune rejuvenation in AD therapy, we reconstituted the immune systems of aged APP/PS1 mice through bone marrow transplantation (BMT). Single cell RNA sequencing (ScRNA-seq) of peripheral blood mononuclear cells (PBMCs) indicated that young BMT reverse the expression of aging- and AD-related genes in multiple cell types of PBMCs. Plasma proteome profiling also indicated the reduction of the plasma level of senescence-associated secretory phenotype (SASP) proteins after young BMT. Young BMT significantly reduced central and peripheral Aβ levels, alleviated brain Aβ plaque burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the aged APP/PS1 mice. These effects occurred with the improved Aβ capacity of peripheral monocytes. Collectively, our study demonstrated that rejuvenation of immune system could decrease brain Aβ deposition and other AD-type pathologies, representing a potential therapeutic approach for AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE235527 | GEO | 2023/06/27

REPOSITORIES: GEO

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Project description:Neuroinflammation is a major contributor to disease progression in Alzheimer´s disease (AD) and is characterized by the activity of brain resident glial cells, in particular microglia cells. However, there is increasing evidence that peripheral immune cells infiltrate the brain at certain stages of AD progression and shape disease pathology. We recently identified CD8+ T-cells in the brain parenchyma of APP-PS1 transgenic mice being tightly associated with microglia as well as with neuronal structures. The functional role of CD8+ T-cells in the AD brain is however completely unexplored. Here, we demonstrate increased numbers of intra-parenchymal CD8+ T-cells in human AD post-mortem hippocampus, which was replicated in APP-PS1 mice. Also, aged WT mice show a remarkable infiltration of CD8+ T-cells, which was more pronounced and had an earlier onset in APP-PS1 mice. To address their functional relevance in AD, we successfully ablated the pool of CD8+ T-cells in the blood, spleen and brain from 12 months-old APP-PS1 and WT mice for a total of 4 weeks using an anti-CD8 antibody treatment. While the treatment at this time of disease stage did neither affect the cognitive outcome nor plaque pathology, RNAseq analysis of the hippocampal transcriptome from APP-PS1 mice lacking CD8+ T-cells revealed highly altered neuronal- and synapse-related gene expression including an up-regulation for neuronal immediate early genes (IEGs) such as the Activity Regulated Cytoskeleton Associated Protein (Arc) and the Neuronal PAS Domain Protein 4 (Npas4). Gene ontology enrichment analysis illustrated that the biological processes “regulation of neuronal synaptic plasticity” and the cellular components “postsynapses” were over-represented upon CD8+ T-cell ablation. Additionally, Kegg pathway analysis showed up-regulated pathways for “calcium signaling”, “long-term potentiation”, “glutamatergic synapse” and “axon guidance”. Therefore, we conclude that CD8+ T-cells infiltrate the aged and AD brain and that brain CD8+ T-cells might directly contribute to neuronal dysfunction in modulating synaptic plasticity. Further analysis will be essential to uncover the exact mechanism of how CD8+ T-cells modulate the neuronal landscape and thereby contribute to AD pathology.

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Young bone marrows transplantation rejuvenates immune cells, attenuate cerebral Aβ accumulation and related pathologies in Alzheimer’s disease model mouse

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