Tau protein as a target for Alzheimer’s disease management

Abstract

Dear Editor, Alzheimer’s disease (AD) is a neurodegenerative disorder and considered the most common form of dementia. Although significant development has been made in AD research during the last few years, much remains to be understood. For instance, no disease-modifying therapeutic agents are available to delay AD onset (Moulder et al., 2013). Five therapies have been approved for AD. Four of these medications are classified together as cholinesterase inhibitors (CIs); these are approved for dementia of the Alzheimer’s type in the mild-to-moderate stage. These include tacrine, donepezil, rivastigmine, and galantamine. Some critics, especially those concerned with conserving rare resources, have alleged that these drugs are not cost effective enough to warrant the expense. Patients and their advocates, looking at the same data but with a different perspective, often come to the opposite conclusion. One the other hand, critics have found to focus on limitations in the methodology of clinical trials and on bias in the way the data are introduced, especially in trials sponsored by drug companies, and have concluded that efficacy of drugs is inflated (Casey et al., 2010). One of the most important problems leading to difficulty in disease management is AD pathology existed in brain cells many years before the appearance of clinical symptoms (Price et al., 2009). AD is distinguished mainly by neuronal loss. Furthermore, it is characterized by two hallmark lesions: amyloid-β-containing plaques and neurofibrillary tangles (NFTs). In AD, NFTs accumulate leaving an impact on some brain regions that are responsible for memory and learning (Hyman et al., 1984). Under pathological conditions, tau protein, which regulates the dynamics of neurons in the brain, becomes abnormally phosphorylated and aggregates into the so-called NFTs (Duyckaerts et al., 2009). Tau protein is considered a target for the development of novel drugs aiming to treat AD as inhibiting the intercellular transfer of tau may slow the progression of tau pathology. Therapeutic strategies for reducing the interneuronal transfer of tau may achieved through different patterns as shown in Fig. 1: inhibiting tau release, reducing accumulation of extracellular tau, or preventing tau uptake (Pooler et al., 2013). Figure 1 Potential therapeutic targets to slow or prevent the spread of tau pathology in the brain (Pooler et al., 2013). Some researchers suggest the utilization of Histone deacetylase (HDAC6) inhibition to enhance tau acetylation as a recent therapeutic strategy for management of AD. HDAC6 inhibitors prevent phosphorylation of tau, so interfering with tau’s ability to aggregate. Lowering HDAC6 activity also enhances microtubule stability and transport, which is thought to stimulate neuronal function (Cook et al., 2014). In conclusion, the available drugs for AD are insufficient to manage this disorder appropriately. There is a high unmet need to develop more advanced drugs. Agents acting on tau protein as a target show some promising outcome in the clinical trials.