Dataset Information

Bone Marrow-Derived GCA⁺ Immune Cells Drive Alzheimer's Disease Progression.

ABSTRACT: Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA⁺ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C-C Motif Chemokine Receptor 10 (CCR10)-dependent manner. Transplanting GCA⁺ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low-density lipoprotein receptor-related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aβ and potentiating neuropathological changes. Importantly, GCA-neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA⁺ immune cells instigating cognitive and memory decline, suggesting that GCA⁺ immune cells can be a potential target for innovative therapeutic strategies in AD.

SUBMITTER: Zhou R

PROVIDER: S-EPMC10754099 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Bone Marrow-Derived GCA<sup>+</sup> Immune Cells Drive Alzheimer's Disease Progression.

Zhou Rui R Wang Liwen L Chen Linyun L Feng Xu X Zhou Ruoyu R Xiang Peng P Wen Jie J Huang Yan Y Zhou Haiyan H

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231110 36

Alzheimer's disease (AD) is an age-related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow-derived GCA<sup>+</sup> immune cells, which secret abundant GCA and increase during aging, preferentially invaded th ...[more]

PMID: 37949676

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Project description:BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.MethodsMouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.ResultsOur results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.ConclusionsThese findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.

Dataset Information

Bone Marrow-Derived GCA⁺ Immune Cells Drive Alzheimer's Disease Progression.

Publications

Bone Marrow-Derived GCA<sup>+</sup> Immune Cells Drive Alzheimer's Disease Progression.

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Dataset Information

Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression.

Publications

Bone Marrow-Derived GCA<sup>+</sup> Immune Cells Drive Alzheimer's Disease Progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Bone Marrow-Derived GCA⁺ Immune Cells Drive Alzheimer's Disease Progression.