Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging.
Mol Neurodegener
; 19(1): 48, 2024 Jun 18.
Article
em En
| MEDLINE
| ID: mdl-38886816
ABSTRACT
BACKGROUND:
Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.METHODS:
To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters.RESULTS:
We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain.CONCLUSIONS:
Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Encéfalo
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Envelhecimento
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Transdução de Sinais
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Interferon Tipo I
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Microglia
Limite:
Animals
Idioma:
En
Revista:
Mol Neurodegener
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos