The Effect of Fragment C of Tetanus Toxin on Memory Deficits in a Rat Model of Alzheimer’s Disease

Year 2023, Volume: 9 Issue: 3, 254 - 259, 30.09.2023

Şeyma Özsoy , Elif Azize Özşahin Delibaş

Abstract

The progression of Alzheimer's disease (AD) is connected to both neuronal elements and immunological mechanisms. Tetanus toxin C-terminal fragment (TTC) has neuroprotective properties. Our objective was to examine the influence of TTC on memory, hippocampal morphology, and inflammation in rats with a STZ-induced AD model. After general anesthesia rats, 3 mg/kg STZ was administered ICV to the right and left lateral ventricles of 5 μl of 12 rats. Six rats were received both lateral ventricules of 0.9% NaCl 5 µl ICV, and others were administered TTC (0.05 flocculation units) in 5 µl ICV one time. No drug was applied to the control group. On the 15th day, all groups underwent a passive avoidance learning (PAL) test, and then brain tissue was collected. Tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) levels within the brain were assessed. Following this, neurons were quantified by employing Cresyl violet staining specifically within the hippocampal CA1 and CA3 regions. In the ICV-STZ group, the PAL latency time significantly reduced, TNF-α levels and IL-6 levels increased, and also the hippocampal CA1 and CA3 neuron numbers decreased. The application of TTC resulted in a significant decrease in the levels of TNF-α and IL-6. Furthermore, it played a role in mitigating the memory impairment caused by ICV-STZ by reducing cell death within the hippocampus. These results suggest that the neuroprotective and anti-inflammatory properties of TTC might have a significant impact on addressing neurodegenerative disorders such as Alzheimer's disease.

Keywords

Alzheimer, streptozotocin, tetanus toxin C-terminal fragment, memory, inflammation

References

• [1] Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015). Alzheimer’s disease. Nat. Rev Dis Primers, 1, 15056.
• [2] Chu, L.W. (2012). Alzheimer’s disease: early diagnosis and treatment. Hong Kong Med J, 18:228–237.
• [3] Walker, K.A., Ficek, B.N. & Westbrook, R. (2019). Understanding the Role of Systemic Inflammation in Alzheimer’s Disease. ACS Chem Neurosci, 10; 3340-3342.
• [4] Netzahualcoyotzi, C., & Tapia, R. (2018). Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo. Sci Rep, 8, 16584.
• [5] Lalli, G., & Schiavo, G. (2002). Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neurotrophin receptor p75NTR. J Cell Biol, 156, 233-239
• [6] Roux, S., Colasante, C., Saint Cloment, C., Barbier, J., Curie, T., Girard, E., ... & Brûlet, P. (2005). Internalization of a GFP-tetanus toxin C-terminal fragment fusion protein at mature mouse neuromuscular junctions. Molecular and Cellular Neuroscience, 30(1); 79-89.
• [7] Mendieta, L., Venegas, B., Moreno, N., Patricio, A., Martínez, I., Aguilera, J., & Limón, I. D. (2009). The carboxyl-terminal domain of the heavy chain of tetanus toxin prevents dopaminergic degeneration and improves motor behavior in rats with striatal MPP(+)-lesions. Neurosci Res, 65(1); 98-106.
• [8] Radenovic, L., Selakovic, V., Olivan, S., Calvo, A. C., Rando, A., Janac, B., & Osta, R. (2014). Neuroprotective efficiency of tetanus toxin C fragment in model of global cerebral ischemia in Mongolian gerbils. Brain Research Bulletin, 101; 37-44.
• [9] Herrando-Grabulosa, M., Casas, C., & Aguilera, J. (2013). The C-terminal domain of tetanus toxin protects motoneurons against acute excitotoxic damage on spinal cord organotypic cultures. J Neurochem, 124, 36–44 Paxinos, G., & Watson, C. (1998).The rat brain in stereotaxic coordinates. Spiral Bound, 4th ed. New York: Academic Press.
• [10] Elibol, B., Terzioglu-Usak, S., Beker, M., & Sahbaz, C. (2019). Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ(1–42)-infused rat model of Alzheimer's disease. Psychiatry and Clinical Psychopharmacology, 29; 379-386.
• [11] Poo, M. M., Pignatelli, M., Ryan, T. J., Tonegawa, S., Bonhoeffer, T., Martin, K. C., ... & Stevens, C. (2016). What is memory? The present state of the engram. BMC biology, 14; 1-18.
• [12] Maruszak, A., & Thuret, S., (2014). Why looking at the whole hippocampus is not enough-a critical role for anteroposterior axis, subfield and activation analyses to enhance predictive value of hippocampal changes for Alzheimer's disease diagnosis. Front Cell Neurosci, 8; 95.
• [13] Padurariu, M., Ciobica, A., Mavroudis, I., Fotiou, D., & Baloyannis, S. (2012). Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer’s disease patients.. Psychiatr Danub, 24; 152-158.
• [14] Clark, I., Atwood, C., Bowen, R., Paz-Filho, G., & Vissel, B. (2012). Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer's disease links numerous treatment rationales Pharmacol Rev, 64; 1004-26.
• [15] Pinton, S., da Rocha, J.T., Gai, B.M., & Nogueira, C.W. (2011) Sporadic dementia of Alzheimer's type induced by streptozotocin promotes anxiogenic behavior in mice. Behav Brain Res, 223;1-6.
• [16] Grieb, P. (2016). Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer’s Disease: in Search of a Relevant Mechanism. Mol Neurobiol, 53(3); 1741-1752.
• [17] Chen, Y., Liang, Z., Blanchard, J., Dai, C. L., Sun, S., Lee, M. H., ... & Gong, C. X.. (2013). A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Molecular neurobiology, 47; 711-725.
• [18] Dickson, D.W. (1997). The pathogenesis of senile plaques. J Neuropathol Exp Neurol, 56; 321-339
• [19] Chang, R., Yee, K.L., & Sumbria, R.K. (2017). Tumor necrosis factor α Inhibition for Alzheimer’s Disease. J Cent Nerv Syst Dis, 9:1179573517709278
• [20] Samuelsson, A. M., Alexanderson, C., Mölne, J., Haraldsson, B., Hansell, P., & Holmäng, A. (2006). Prenatal exposure to interleukin‐6 results in hypertension and alterations in the renin–angiotensin system of the rat. The journal of physiology, 575(3); 855-867.
• [21] Patel, N. S., Paris, D., Mathura, V., Quadros, A. N., Crawford, F. C., & Mullan, M. J. (2005). Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. Journal of neuroinflammation, 2; 1-10.
• [22] Bayart, C., Mularoni, A., Hemmani, N., Kerachni, S., Jose, J., Gouet, P., ... & Le Borgne, M. (2022). Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production. Pharmaceuticals (Basel), 15(6);756.
• [23] Patricio-Martínez, A., Mendieta, L., Martínez, I., Aguilera, J., & Limón, I. D. (2016). The recombinant C-terminal fragment of tetanus toxin protects against cholinotoxicity by intraseptal injection of β-amyloid peptide (25–35) in rats. Neuroscience, 315; 18-30.