Dataset Information

MicroRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

ABSTRACT: Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron-specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD-associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA-425 (miR-425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque-associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR-425, a neuronal-specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR-425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR-425-deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR-425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal-specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s).

SUBMITTER: Hu YB

PROVIDER: S-EPMC8520725 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

Hu Yong-Bo YB Zhang Yong-Fang YF Ren Ru-Jing RJ Dammer Eric B EB Xie Xin-Yi XY Chen Shi-Wu SW Huang Qiang Q Huang Wan-Ying WY Zhang Rui R Chen Hong-Zhuan HZ Wang Hao H Wang Gang G

Aging cell 20210912 10

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron-specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD-associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA-425 (miR-425) levels and this change leads to focal brain mic ...[more]

PMID: 34510683

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Project description:The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.

Dataset Information

MicroRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

Publications

microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

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