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Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures.


ABSTRACT: Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aβ. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aβ1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

SUBMITTER: Aloi MS 

PROVIDER: S-EPMC9990295 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures.

Aloi Macarena S MS   Prater Katherine E KE   Sánchez Raymond E A REA   Beck Asad A   Pathan Jasmine L JL   Davidson Stephanie S   Wilson Angela A   Keene C Dirk CD   de la Iglesia Horacio H   Jayadev Suman S   Garden Gwenn A GA  

Journal of neuroinflammation 20230307 1


Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathog  ...[more]

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