Decreased Netrin-1 and Correlated Th17/Tregs Balance Disorder in Aβ1–42 Induced Alzheimer’s Disease Model Rats

Abstract

There is increasing evidence indicating that inflammation represents a key pathological component of Alzheimer’s disease (AD). A possible factor that may contribute to this process is netrin-1, a neuronal guidance molecule. This molecule has been shown to exert an unexpected immunomodulatory function. However, the potential changes and correlations of netrin-1 with T helper 17/regulatory T cells (Th17/Tregs) as related to inflammation in AD has yet to be examined. In this study, netrin-1 and Th17/Tregs balance were investigated, and the relationship among netrin-1, Th17/Tregs and cognitive function were analyzed in a rat model of AD. In this model, a bilateral intracerebroventricular administration of Amyloid β 1-42 (Aβ 1–42 ) was used to produce spatial learning and memory deficits, as well as increased neuronal apoptosis, which were detected 7 days after injection for AD7d group and 14 days for AD14d group. Netrin-1 concentrations were significantly down regulated in both serum and cerebrospinal fluid (CSF) of these AD rats, effects which were strongly correlated with cognitive deficits. Increased levels of interleukin (IL)-17 and deceased IL-10 were observed in both the circulation and CSF and were also correlated with the percent of time spent in the target quadrant of AD in these rats. These changes resulted in netrin-1 concentrations being negatively correlated with IL-17 but positively correlated with IL-10 concentrations in the serum and CSF. We also found that the Th17/Tregs balance was disrupted in these AD rats. Collectively, these findings reveal that the reduction in netrin-1 and the correlated disruption of Th17/Tregs balance in AD rats may diminish the immunosuppressive effect of netrin-1 on Th17/Tregs in AD pathogenesis.

Netrin-1 Ameliorates Postoperative Delirium-Like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood-Brain Barrier Permeability

“…Early studies found that NTN-1 interacts with the UNC-5B receptor expressed on the surface of the white blood cells and inhibits the migration of the white blood cells (Ly et al, 2005). In Alzheimer's disease (AD) rats (Sun et al, 2019), it has been demonstrated that NTN-1 concentrations in serum were positively correlated with the systemic expression of IL-10 (Mosser and Zhang, 2008). Moreover, in acute peritonitis and acute colitis models, NTN-1 inhibits the migration of inflammatory cells and induces the M2 polarization phenotype of macrophages (Mirakaj et al, 2011;Aherne et al, 2012).…”

Netrin-1 Ameliorates Postoperative Delirium-like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood Brain Barrier Permeability

“…Early studies found that NTN-1 interacts with the UNC-5B receptor expressed on the surface of white blood cells and inhibits the migration of white blood cells [19]. In Alzheimer's disease (AD) rats [51], it has been demonstrated that NTN-1 concentrations in the serum were positively correlated with the systemic expression of IL-10, one of the most important mediators in the anti-in ammatory activity [52]. What is more, in acute peritonitis and acute colitis models, NTN-1 inhibits the migration of in ammatory cells and induces the M2 polarization phenotype of macrophages [53,54].…”

Expression of Genes Involved in Axon Guidance: How Much Have We Learned?

“…The knock-down of Netrin-1 increased the level of Aβ in AD model mice, while the over-expression of Netrin-1 decreased its level, revealing that Netrin-1 had a protective role against Aβ [175]. It was also recently found that the level of Netrin-1 was decreased in both the serum and cerebrospinal fluid of an Aβ 1-42 -induced AD model rat, which further showed the association of Netrin-1 to the progression of AD [176]. Some scientists further demonstrated that treatment with Netrin-1 improved cognition in AD model mice [171,172].…”