Aging Differentially Affects the Loss of Neuronal Dendritic Spine, Neuroinflammation and Memory Impairment at Rats after Surgery

Yuan, Long; Liu, Shuli; Peng, Mingchao; Tan, Chang; Liao, Qin; Duan, Kai-Ming; Ouyang, Wen; Tong, Jianbin

doi:10.1371/journal.pone.0106837

Cited by 56 publications

(33 citation statements)

References 32 publications

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“…The incidence of PND in middle‐aged patients is 19.2% and up to 52% in senior patients . Increased susceptibility to PND has also been found in aged animals . However, the mechanisms underlying the increased susceptibility to PND in elderly individuals remained largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice

Zhao

Deng

Shen³

et al. 2019

Ann Clin Transl Neurol

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Background Postoperative neurocognitive disorder (PND) is a severe postoperative complication with no effective therapy that affects up to 19–52% of senior patients. Age and surgery type have been identified as risk factors. However, what caused the increased risk in the elderly is poorly understood. Methods We utilized a PND model in aged mice undergoing experimental laparotomy with general anesthesia to evaluate the causal relationship between hyperhomocysteinemia and increased PND susceptibility. PND was assessed by Novel Object Tasks, Fear Conditioning Tests, and Barnes Maze Tests. Serum homocysteine (Hcy) as well as vitamin B12 and folate acid levels were tested before, immediately after surgery and from day 1 to day 29 after surgery by ELISA. The effectiveness of preventative strategy including diet supplementation of vitamin B12 + folic acid (Vit B12 + FA) and S‐adenosylmethionine (SAM) injection targeting hyperhomocysteinemia were also tested. Results PND in aged mice lasted for at least 2 weeks after experimental laparotomy, which was not observed in young adult mice. Serum Hcy results indicated a significant correlation between postoperative cognitive performance and perioperative Hcy level. Preoperative supplementation with VB12 and folic acid (FA) in the diet or S‐adenosylmethionine (SAM) injection reduced perioperative serum Hcy level and inhibited the development of PND in aged mice. Conclusions Serum homocysteine accumulation is a fundamental cause for increased susceptibility of PND in aged mice. Preoperative diet supplementation of VitB12 + FA can effectively reduce PND in aged mice, which may be a promising prophylaxis treatment in clinical settings.

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Section: Introductionmentioning

confidence: 99%

Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice

Zhao

Deng

Shen³

et al. 2019

Ann Clin Transl Neurol

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“…Additionally, Rosczyk et al have demonstrated that locomotor activity is not depressed in either adult or aged mice following sham operation (minor abdominal surgery), which reveals that the decrease in locomotion is not due to minor surgical procedures [20]. It is likely that a more “major” surgery (partial hepatectomy) would induce a state of neuroinflammation that could result in sickness behavior [2, 7, 21-25]. …”

Section: Introductionmentioning

confidence: 99%

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer’s disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression.

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“…Lots of studies have been done to investigate its risk factors, pathological mechanisms, and methods of prevention and treatment[ 2 ]. So far, neuroinflammation[ 6 , 7 , 8 ], oxidative stress[ 9 , 10 ] and synaptic changes[ 11 , 12 ] all have been reported to contribute to the development of POCD. Age is described as the only risk of long-term POCD[ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age

et al. 2017

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Occurrence of postoperative cognitive dysfunction (POCD) is age-dependent and heterogenous. Factors deciding the occurrence of POCD in patients of the same age undergone same surgeries remain unclear. Here we investigated the effects of pre-existing weakness on the occurrence of POCD in mice of the same age. Pre-existing weakness of mice was induced by intraperitoneal injection of lipopolysaccharide (8mg/kg) and was evaluated by physical frailty index (by open field test), neuroinflammation level (by Iba1 immunostaining and inflammatory factors TNF-α and IL-1β), and neuronal activity (by p-CREB immunostaining). POCD was induced by partial hepatolobectomy and was evaluated by puzzle box test and Morris water maze test. The brains were collected to detect the levels of neuroinflammation, synaptophysin and NMDA receptor subunits NR2A, NR2B and NR1 (by western blot), and oxidative stress (by Dihydroethidium). Compared to the normal adult mice of the same age, LPS pretreated mice had increased physical frailty index, higher levels of neuroinflammation, and lower neuronal activity. Partial hepatolobectomy induced obvious impairments in executive function, learning and memory in LPS pretreated mice after surgery, but not in normal mice of the same age. Partial hepatolobectomy also induced heightened neuroinflammation, obvious loss of NMDA receptor subunits, strong oxidative stress in LPS pretreated mice on the 1st and 3rd postoperative day. However, the POCD-associated pathological changes didn’t occur in normal mice of the same age after surgery. These results suggest that pre-existing weakness is critical for the occurrence of POCD in mice of the same age.

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Aging Differentially Affects the Loss of Neuronal Dendritic Spine, Neuroinflammation and Memory Impairment at Rats after Surgery

Cited by 56 publications

References 32 publications

Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice

Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age

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