Tau Aggregation Inhibitors

Tau is a protein mainly found in the central nervous system and, more specifically, in the axonal compartment of neurons. Human tau protein is expressed by the single microtubule-associated protein tau (MAPT) gene located at chromosome 17. Despite its small size, tau protein plays a very important role in the proper functioning of the brain. This protein stabilizes the internal skeleton of neurons, forming a solid microtubule structure. One of the functions of the microtubule is to help transport nutrients and other essential substances from one part of the neuron to another. 

In certain pathological situations, tau protein may undergo modifications that can result in the generation of atypical aggregates (i.e., large clusters usually formed by smaller misfolded particles) that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as tauopathies. Tauopathies are characterized by excessive tau aggregates in neurons and glial cells. The most commonly recognized tauopathy is Alzheimer disease (AD). In individuals with Alzheimer disease, tau proteins are misfolded and abnormally shaped, causing the microtubule structure to collapse. Other known tauopathies include Huntington disease (HD), Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD).  

Tau aggregation refers to the abnormal association of the protein into larger clusters, which tend to be very insoluble, or difficult to resolve. The accumulation of tau aggregates in neurons directly correlates with microtubule dysfunction, thereby leading to neuronal degeneration and loss. Many reports have shown that the accumulation of tau aggregates is caused by post-translational modifications, including tau hyperphosphorylation (i.e., an increase in either the number of phosphorylated sites per tau molecule), acetylation (i.e., a chemical reaction within the protein during which a hydrogen atom is substituted for an acetyl group), and gene mutation (e.g., frameshift mutations associated with AD). The misfolded tau is self-assembled and forms tau oligomers (i.e., collection of a small number of repeating units, up to a few hundred), which can accumulate to form tau aggregates. 

There is a specific region of tau that is responsible for microtubule binding and contains a large number of lysines, which is a positively charged amino acid. The positive charge of lysine allows tau to bind with the negatively-charged microtubules. When tau is abnormally hyperphosphorylated, the balance is disrupted and tau dissociates from microtubules. In this state, tau begins to aggregate.

Tau aggregation inhibitors are pharmacologic agents that aim to inhibit tau aggregation and prevent progression of certain conditions, like Alzheimer disease. There are several compounds that have shown promising results in in-vitro studies, such as methylene blue, emerging nutraceutic compounds (e.g., oleocanthal, curcumin, thiophene), diazodinitrophenol, and polythiophene compounds. However, thus far, methylene blue derivatives and curcumin are the only molecules that have advanced to clinical trials. The main focus of research has been on methylene blue, particularly its derivative called hydromethylthionine mesylate (HMTM), which is currently in phase III clinical trials. 

Tau aggregation inhibitors are designed to prevent or disrupt the process of tau protein misfolding and aggregation in neurodegenerative diseases. They work by targeting various stages of the aggregation process to prevent or minimize the formation of tau aggregates, thereby slowing disease progression. There are two main approaches to how these inhibitors work: by directly binding to tau (thereby altering its shape) or by breaking down existing aggregated tau complexes. 

Inhibitors of tau aggregation, like HMTM, directly bind to the domain on the tau protein that contains high quantities of lysine, effectively blocking interactions between tau proteins themselves. In recent studies, in genetically modified tau mouse models, HMTM reduced tau pathology and behavioral impairments. Phase II and III trials conducted in humans have shown that HMTM is safe and has a low-risk side effect profile. Notably, HMTM at a dose of 16 milligrams per day (mg/day) revealed a statistically significant benefit in the cognitive and functional performance of individuals with moderate AD. Notably, tau aggregation inhibitors do not reverse pathology, especially if it is severe, but may help prevent further progression of disease.

Other tau inhibitors work by breaking existing tau aggregates, effectively disaggregating them into individual tau molecules. This process helps to reverse the harmful effects of tau aggregation and reduces the burden on brain cells. For example, curcumin, which is now undergoing clinical trials, attaches to low-strength tau and breaks down tau accumulations.