Tau as a Therapeutic Target for Alzheimer’s Disease
Yo Sup Keum
Introduction: Alzheimer’s Disease (AD) is a major age-related, progressive, neurodegenerative disorder and is the fourth leading cause of death in developed nations. Currently available medications and therapeutic options only treat the symptoms or have focused on ameliorating the symptoms as well as reducing the rate of progression of AD.2,3 The main cause of AD is excessive generation of reactive oxygen species that leads to several harmful effects including DNA, lipid, and protein damage.1 Aggregation of tau proteins is one of the key events that cause oxidative stress. The tau therapy targets the misfolded hyperphosphorylated tau, which is the pathologic form of protein, and reduce its levels. The goal of this study is to investigate the cutting-edge tau therapies that can prevent, treat, or reverse the progression of AD. Methods: A team of researchers engineered single-chain variable fragments (scFvs) derived from HJ8.5 with variable linker lengths, all specific to human tau. They tested the efficacy of the scFvs by adeno-associated virus-mediated gene transfer to the brain of the tau-expressing transgenic mice.4 Another team of researchers developed tau vaccine, AADvac1, against pathological tau proteins. They utilized western blot analysis to test whether the antibodies elicited by the vaccine could recognize pathological tau protein in the brains with AD.5 Another study investigated the effect and mechanism of folic acids on tau phosphorylation in diabetic mice. Tau hyperphosphorylation was assessed by Western blot and immunohistochemistry using antibodies against phosphorylated site (Ser396) on tau.6 Results: The scFvs significantly reduced levels of hyperphosphorylated, aggregated tau in hippocampal regions of brain tissue of the transgenic mice. The scFVs appear to clear tau, prevent tau uptake into neurons, and inhibit its seeding without causing proinflammatory response.4 The tau vaccine, AADvac1, was successful in generating antibodies that target pathologic form of tau.5 Folic acid reduced tau hyperphosphorylation at Ser396 of tau proteins in the brain of diabetes mellitus (DM) mice.6 Conclusions: All the three treatment strategies of AAV mediated scFvs, Tau vaccine AADvac1, and folic acid were successful in targeting the hyperphosphorylated tau. Among these three, AAV mediated scFvs and folic acid reduced the level of the pathologic tau. These treatment strategies show promising potential in prevention and possible cure of Alzheimer’s disease.
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- Ising C, Gallardo G, Leyns CEG, et al. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J Exp Med. 2017.
- Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123-134.
- Zheng M, Zou C, Li M, Huang G, Gao Y, Liu H. Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice. Int J Mol Sci.2017;18(4).