Tau Protein: Targets And Development Against Alzheimer’s Disease

The clinical manifestations of Alzheimer's disease (AD) and associated human tauopathies are driven by tau neuronal and glial abnormalities. Tau, a microtubule-associated protein is inherently disordered due to its lack of a stable structure and great flexibility. Intracellular inclusions of fibrillar tau with a sheet shape accumulate in the brains of individuals with AD and other tauopathies. As a result, tau separation from microtubules and tau transition from a disordered state to an inappropriately aggregated state are critical steps before the start of tau-related illnesses. Many studies have demonstrated that this shift is triggered by post translational changes such as hyperphosphorylation and acetylation. Before the development of tau inclusions, the misfolded tau self-assembles and forms a tau oligomer. Animal and clinical research utilising human samples has shown that tau oligomer development contributes to neuronal death. During tauopathies, tau seeds are released from cells and absorbed into neighbouring cells, resulting in the spread of abnormal tau aggregation. Thus, Tau has become both a physiological and pathological target for AD treatments during the last decade. Evidence reveals many potential techniques for preventing tau-mediated toxicity: (1) direct suppression of pathological tau aggregation; (2) inhibition of tau post-translational changes that occur before pathological tau aggregation; (3) inhibition of tau propagation; and (4) microtubule stabilisation. Aside from traditional low-molecular-weight compounds, newer drug discovery approaches, such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody based drugs), provide alternative pathways to preventing the formation of abnormal tau. Suppression of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminl)-L-serine/threonine hydrolase, inhibition of tau aggregation, active and passive immunotherapies, and tau silencing using antisense oligonucleotides; in several animal models, have shown the capacity to prevent or minimise tau lesions and treat either cognitive or motor impairment. Immunotherapy, which has already reached the clinical stage of drug development, is the most advanced technique for treating human tauopathies. Tau vaccines or humanised antibodies are designed to target a range of tauspecies in both intracellular and extracellular environments. Some of them recognise the amino- or carboxy-terminus, while others have proline-rich areas or microtubule binding domains that they can attach to. In this review, we examine various clinical targets for the treatment of tauopathies as well as the various molecules researched as tau inhibitors that can be used in AD. Furthermore, we explore the efficacy of some of the prominent molecules in clinical studies for tau-targeted therapies research.