Tau in Alzheimer’s Disease, FTD, and Other Tauopathies

To the untrained eye, diseases like frontotemporal dementia (FTLD) and Alzheimer’s disease (AD) may appear extremely similar. While this is true in terms of disease presentation, the synchronicities are even evident in how these diseases behave on a molecular level. What is it that these two diseases share? The answer: tau, a microtubule-binding protein that is highly expressed in central nervous system (CNS) cells like neurons and glia. 

Neurodegenerative diseases like FTLD and AD are often marked by cognitive decline in a way that is associated with memory loss and behavioral changes. On a systems level, one can consider how they differ by examining which brain regions are particularly affected by the disease. When we shrink down to the molecular level, however, we observe specific perturbations of the tau protein that can be used to differentiate between the two similarly-presenting diseases.

Under homeostatic conditions, tau is a flexible, intrinsically disordered protein that acts as a master regulator of microtubules, the cargo highways of the cell. However, during disease states, tau exhibits two primary problems. First, tau loses its ability to stabilize microtubules through loss of binding affinity. Once tau is detached from microtubules, the free tau will aggregate into paired helical filaments (PHF) that eventually become neurofibrillary tangles (NFTs). These NFTs prevent cellular activity from proceeding as normal, shutting down the microtubule-based cargo networks in the cell, and impeding overall cellular function. This is the basic mechanistic model of how tau causes dysfunction, and researchers are still working to unravel how this overall causes disease.

NFTs are a hallmark of AD in all cases, and likewise are present in specific subsets of FTLD. Tau NFTs make up about 40% of all FTLD cases, with other proteins like TDP-43 and FUS being dysregulated in other cases. What distinguishes AD from FTLD-tau on a molecular level is another protein that is implicated in AD cases: APP, the amyloid beta precursor protein. This protein breaks down into peptides around 36-43 amino acids in length that form plaques referred to as amyloid beta, or Aβ plaques. These plaques are never seen in FTLD, but are always present in AD. 

What does this mean for researchers?

When examining the tau-related mechanisms that cause specific diseases, there are many dimensions to consider to hone in on what becomes dysregulated. Not only does the specificity of the tau antibody matter so that researchers can visualize exactly where in brain tissue this protein aggregates, the specific epitope targeted becomes highly valuable to resolving these mechanisms and distinguishing the diseases. 

Researchers must measure the presence of tau using an antibody that is specific to an isoform or an antibody that recognizes a non-variable region of tau (which we can refer to as a pan-tau antibody) to help monitor location and levels of this protein in CNS tissue. 

However, most current research highlights the importance of post-translational modification (PTM) on the development of so-called tauopathies like FTLD and AD, so it becomes necessary to monitor the PTM status of tau – especially its phosphorylation status – to truly uncover its mechanisms. 

The catch? There are around 85 phosphorylation sites, and it is not currently known which sites regulate which behaviors. The leading school of thought is that hyperphosphorylation of tau decreases microtubule binding affinity and promotes aggregation, but the precise mechanisms are still unclear. Thus, targeting tau becomes extremely complex and requires site-specific antibodies to help unravel the mechanisms that promote disease.

Are FTLD and AD the only diseases that implicate tau?

Because tau is an essential part of the biochemical machinery that allows CNS tissue to function properly, there is a range of diseases called tauopathies which implicate this specific protein as the molecular culprit for dysfunction. Among these diseases are dementias in other areas of the brain, which are remarked at times by tau aggregation, as well as isoform-specific tauopathies like Pick’s disease and progressive supranuclear palsy. Even traumatic injuries can result in tau-driven disease, such as chronic traumatic encephalopathy (CTE). 

Between the many different functions and diseases related to tau, mystified by the combinatorial effect of 85 relevant phospho-sites, targeting this protein becomes challenging. This is why HUABIO offers a host of tau products, including over 50 different antibodies to target this multifaceted protein.