Su Min Cho

Introduction: Alzheimer’s disease is currently the leading cause of dementia and continues to rise in prevalence as the population ages[1]. Tau proteins are believed to play a major role in various neurodegenerative diseases including Alzheimer’s disease[1,2]. Tau is normally a soluble, microtubule-binding protein that stabilizes the microtubules of axons in the central nervous system[3,4]. Hyperphosphorylation of tau causes tau to disengage from microtubules, resulting in both destabilizations of microtubules and aggregation of tau that lead to neurodegeneration[1,4]. Studies done by the Zhang group have found that selenomethionine (Se-Met) reduced the levels of total tau and hyperphosphorylated tau and improved cognition and memory in Alzheimer’s disease mice model[5]. This finding suggest a possible therapeutic agent for treatment of Alzheimer’s disease. Methods: The Alzheimer’s disease mice model (3xTg-AD) was utilized[5]. The 3xTg-AD mice were treated with 6 ug/mL Se-Met in their drinking water for 12 weeks while the control mice and wild-type mice were given normal water[5]. Spatial learning was assessed using morris water maze while learning and memory were assessed using the step-down test mice[5]. After a 12- week period, their brains were removed[5]. Protein concentrations were determined using western blot and bicinchoninic acid assay (Sigma-Aldrich)[5]. Immunofluorescent staining was also used   to compare tau levels[5]. The data was analyzed using a program called GraphPad Prism[5]. Results: Se-Met was found to improve spatial memory deficits in 3xTg-AD mice based on the reduced escape latency times from the morris water maze test (p<0.01)[5]. Both western blot analysis and immunofluorescent stain analysis of tau proteins showed a significant reduction of total tau and hyperphosphorylated tau in mice treated with Se-Met (p<0.05)[5]. There was a decrease in activity of GSK3β kinase (major regulator of tau Hyperphosphorylation) as shown by an increased protein ratio of p-GSK3β/GSK3β (p<0.05)[5]. There was also an increased activity of Akt proteins (inactivator of GSK3β) as shown by an increased ratio of p-Akt/Akt (p<0.05)[5]. The decreased activity of GSK3β and increased activity of Akt suggest a mechanism by which Se-Met induces dephosphorylation of tau in aged 3xTg-AD mice[5].  Conclusions: The study shows a possible benefit of Se-Met in the alleviation of Alzheimer’s disease in humans. Se-Met appears to directly modulate the Akt/GSK3B pathway in order to reduce the levels of both total tau and hyperphosphorylated tau. This may re-stabilize the neuronal microtubules and reduce the presence of tau aggregates to alleviate and treat the neurodegenerative effects of Alzheimer’s disease.

1. Dammer, , Yolcu, D., Kukuk, L., et al. Selection and Characterization of Tau Binding ᴅ- Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. PLoS One. 11(12) (2016).
2. Weiner, W., Veitch, D. P., Aisen, P. S., et al. The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimer’s & Dementia. 9, e111-e194 (2013).
3. Bakota, , Ussif, A., Jeserich G., et al. Systemic and network functions of the microtubule-associated protein tau: Implications for tau-based therapies. Moelcular and Cellular Neuroscience. In press, Corrected Proof (2017).
4. Duan, R., Jonasson, E. M., Alberico, E. O., et al. Interactions between Tau and different conformations of tubulin: Implications for Tau function and mechanism. Journal of Molecular Biology. In Press, Accepted Manuscript (2017).
5. Zhang, H., Wu, Q. Y., Zheng, R., et al. Selenomethionine Mitigates Cognitive Decline by Trageting Both Tau Hyperphosphorylation and Autophagic Clearance in an Alzheimer’s Disease Mouse model. Journal of Neuroscience. 37 (9); 2449-2462 (2017).