Tau Protein and Alzheimer’s Disease: What’s the Connection?
Reviewed by Sharyn Rossi, PhD
Tau is a small protein with a short name and a big reputation. It is associated with many brain diseases, including Alzheimer’s disease.
Predominantly found in brain cells (neurons), the tau protein serves multiple functions in healthy brain cells. A very important one is stabilization of the internal microtubules, which help transport nutrients and other important substances from one part of the nerve cell to another.
In Alzheimer’s disease, however, tau becomes misfolded and abnormally shaped. No longer fit to carry out its usual job, tau takes on characteristics that are potentially very damaging—leading to Alzheimer’s and other diseases.
What is Tau?
Before we explain the different types of tau, it is important to understand the structure of the brain’s cells.
Our cells contain a “skeleton” made of tube-like structures. These structures, called microtubules, also are the cell’s highway system. Neurons are brain cells that send material through long extensions called axons. Axons also contain microtubules.
Tau protein is found mostly in neurons and has many roles in healthy brain cells. One of its roles is to support the microtubule highway system. In mice genetically designed to not produce tau protein, their brain cells do not function properly. Abnormal tau has been found in several severe human brain diseases.
In Alzheimer’s disease, tau proteins change. The changed tau proteins stop supporting microtubules. Instead, they stick to each other in tangles. These tangles look like threads in brain cells. They are called neurofibrillary tangles. Tau tangles disrupt how neurons function.
Video: How Alzheimer’s Changes the Brain
Brain Diseases Associated with Tau
Tau tangles are linked to several brain diseases. “Tauopathies” was coined as an umbrella term for neurodegenerative disorders characterized by tau deposits in the brain. Currently, more than 26 different tauopathies have been identified, including Alzheimer’s, chronic traumatic encephalopathy, Pick’s disease, frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy, and corticobasal degeneration. All of these forms of dementia are severe and progressive.
Different Forms of Tau
The abnormal tau proteins found in these neurodegenerative diseases are not identical, although they are related. Larger tau protein is spliced into smaller segments that result in six different human forms. Each tauopathy is classified by the type of tau predominantly found in the aggregates.
After tau has been created from DNA, chemical activities in the brain further modify it in several ways. These chemical alterations of tau change its properties. No longer fit to carry out its usual job, it takes on characteristics that are potentially very damaging. This form of tau no longer sticks together in the same way. Instead, the fabric of connected tau proteins comes apart and reassembles in a disorganized, messy tangle that accumulates in brain cells and is not effectively disposed of through the cell’s usual ways of removing “trash.”
Besides the microtubular form, which is composed of many tau molecules, tau also exists in smaller versions, called oligomers, which are made up of a few tau proteins. The smaller forms of tau circulate among the neurons, interfering with cellular function. They are found in brains that are developing Alzheimer’s decades before the disease can be detected clinically.
What Causes Tau Buildup?
Tau tangles start in the brainstem, which connects the brain to the spinal cord. From the brainstem, tau tangles spread upward. In their path are two brain regions that are key to memory. One region is the entorhinal cortex, which is a gateway to the second region, the hippocampus. Some of the earliest damage in Alzheimer’s disease is seen in brain cells from the entorhinal cortex. From there, damage moves to the hippocampus.
The amount of abnormal tau in the brain of someone with Alzheimer’s disease is linked to disease stage and severity and seems to be a more accurate predictor, and earlier indicator, of cognitive decline than amyloid-beta.
Medical Tests for Tau
The field has quickly progressed to the point where tau biomarkers can be targeted to almost any stage of Alzheimer’s, from the earliest amyloid-beta accumulation to advanced neurodegeneration, which can span 20 years or longer.
Two commercially available blood tests can detect abnormal tau in Alzheimer’s disease. One test, the Simoa p-Tau181, was developed by Quanterix Corporation and can be ordered by physicians.
The second blood test that includes tau is PrecivityAD2, developed by C2N Diagnostics. These tests measure tau that has undergone molecular changes, known as phosphorylation, which correlates with Alzheimer’s disease. Both tests also detect another Alzheimer’s disease protein called amyloid-beta.
Specialized imaging tools can also be used to detect tau. First, an agent is injected into a vein that contains a molecule that can bind to tau in the brain. The second step is a positron emission tomography, or PET, scan. This scan detects where the agent attached to tau in the brain. Clinicians can look at images from these scans to see the amounts and locations of tau.
PET scans can identify and measure the amount of accumulation of both tau and amyloid-beta. Amyloid PET scan tracers, which are already FDA-approved, are often used to screen candidates for Alzheimer’s clinical trials. They identify the presence of disease and can help measure disease progression. However, amyloid PET scans won’t identify the stage of dementia because of amyloid’s early accumulation. Tau PET scans, on the other hand, provide a biomarker measurement that meaningfully indicate disease progression.
Tau PET scan tracers have been developed and evidence supports tau PET scanning as a biomarker that reflects the stage of neurodegeneration associated with Alzheimer’s disease. The first of the tau PET tracers to be approved by the US FDA is F-18 flortaucipir. Many Alzheimer's clinical trials include tau PET scans as a potential biomarker of disease severity.
Recent BrightFocus-Funded Tau Research
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