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Updated: Jul 26, 2025
A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
TAK1 Reduces Surgery-induced Overactivation of RIPK1 to Relieve Neuroinflammation and Cognitive Dysfunction in Aged
Yuhan Zhang1, Yang Su2, Ziheng Wang2
1Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, 221009, China.
Background:
Postoperative cognitive dysfunction (POCD) is a common clinical complication in elderly patients, but its underlying mechanism remains unclear. Receptor-interacting protein kinase 1 (RIPK1), a key molecule mediating necroptosis and regulated by transforming growth factor β-activated kinase 1 (TAK1), was reported to be associated with cognitive impairment in several neurodegenerative diseases. This study was conducted to investigate the possible role of TAK1/RIPK1 signalling in POCD development following surgery in rats.
Methods:
Young (2-month-old) and old (24-month-old) Sprague-Dawley rats were subjected to splenectomy under isoflurane anaesthesia. The young rats were treated with the TAK1 inhibitor takinib or the RIPK1 inhibitor necrostatin-1 (Nec-1) before surgery, and old rats received adeno-associated virus (AAV)-TAK1 before surgery. The open field test and contextual fear conditioning test were conducted on postoperative day 3. The changes in TNF-α, pro-IL-1β, AP-1, NF-κB p65, pRIPK1, pTAK1 and TAK1 expression and astrocyte and microglia activation in the hippocampus were assessed.
Results:
Old rats had low TAK1 expression and were more susceptible to surgery-induced POCD and neuroinflammation than young rats. TAK1 inhibition exacerbated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in young rats, and this effect was reversed by a RIPK1 inhibitor. Conversely, genetic TAK1 overexpression attenuated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in old rats.
Conclusion:
Ageing-related decreases in TAK1 expression may contribute to surgery-induced RIPK1 overactivation, resulting in neuroinflammation and cognitive impairment in old rats.
Insights
Decreased transforming growth factor β-activated kinase 1 (TAK1) expression in aged rats exacerbates surgery-induced cognitive dysfunction by promoting receptor-interacting protein kinase 1 (RIPK1) overactivation and neuroinflammation.
Area of Science:
- Neuroscience
- Molecular Biology
- Gerontology
Background:
- Postoperative cognitive dysfunction (POCD) is a prevalent complication in elderly patients, with unclear underlying mechanisms.
- Receptor-interacting protein kinase 1 (RIPK1) is implicated in cognitive impairment and regulated by transforming growth factor β-activated kinase 1 (TAK1).
Purpose of the Study:
- To investigate the role of TAK1/RIPK1 signaling in the development of POCD following surgery in rats.
- To explore the impact of age on TAK1/RIPK1 pathway activity in the context of surgical stress.
Main Methods:
- Young and old rats underwent splenectomy under anesthesia.
- Pharmacological inhibition of TAK1 or RIPK1 in young rats, and genetic TAK1 overexpression in old rats were performed.
- Cognitive function, neuroinflammation markers (TNF-α, pro-IL-1β), and signaling pathway components (pRIPK1, pTAK1) in the hippocampus were assessed.
Main Results:
- Old rats exhibited lower TAK1 expression and were more susceptible to surgery-induced POCD and neuroinflammation compared to young rats.
- TAK1 inhibition worsened POCD and neuroinflammation in young rats, an effect reversed by RIPK1 inhibition.
- TAK1 overexpression in old rats attenuated surgery-induced POCD, RIPK1 activation, and neuroinflammation.
Conclusions:
- Age-related reduction in TAK1 expression contributes to surgery-induced RIPK1 overactivation.
- This pathway dysregulation leads to neuroinflammation and cognitive impairment in aged individuals post-surgery.
