Aging Promotes Chronic Stress-Induced Depressive-Like Behavior by Activating NLRP1 Inflammasome-Driven Inflammatory...

Area of Science:

• Neuroscience
• Immunology
• Gerontology

Background:

• The NLRP1 inflammasome is implicated in neurological disorders and chronic stress-induced depression.
• Age is a known risk factor for depression, but its underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of NLRP1 inflammasome in age-related depression.
• To explore the NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling pathway in aged mice subjected to chronic stress.

Main Methods:

• Establishment of depression models in young and aged mice using chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS).
• Assessment of depressive-like behaviors, locomotor activity, and hippocampal expression of NLRP1 inflammasome components, inflammatory cytokines, CXCL1, CXCR2, and BDNF.
• Hippocampal Nlrp1a knockdown in aged mice to evaluate its therapeutic potential.

Main Results:

• Aged mice displayed exacerbated depressive-like behaviors and reduced locomotor activity compared to young mice.
• Hippocampal NLRP1 inflammasome, inflammatory cytokines, CXCL1, and CXCR2 expression increased with age and chronic stress.
• Chronic stress led to lower hippocampal BDNF levels in aged mice, which were restored by Nlrp1a knockdown.
• Nlrp1a knockdown alleviated depressive behaviors and normalized inflammatory and BDNF levels in aged mice.

Conclusions:

• NLRP1 inflammasome activation, along with CXCL1/CXCR2 upregulation and BDNF reduction, contributes to age-related depression under chronic stress.
• Targeting the NLRP1 inflammasome pathway offers a potential therapeutic strategy for mitigating age-associated depressive disorders.