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The Most Obvious Tau Aggregates in Tauopathies, the Neurofibrillary Tangles, are not the Primary Cause of Harm

Altered proteins build up in the aging brain, forming solid deposits. The most prominent of them are amyloid-β, altered forms of tau, and α-synuclein, giving rise to amyloidosis, tauopathies, and synucleinopathies respectively. Some conditions mix and match: Alzheimer's disease is both an amyloidosis and a tauopathy. To further muddy the waters, any aging brain far enough along in the process to exhibit full-blown neurodegeneration will also exhibit significant levels of all of the other forms of dysfunction caused by aging.

Present thinking on the roots of protein aggregation conditions is fairly diverse. Insofar as there is a consensus, the root causes are considered to include issues such as failing cellular maintenance processes, failure of the drainage of cerebrospinal fluid as a way to export waste to the rest of the body, infection by pathogens capable of generating more of these unwanted proteins, and failure of the immune system - in defending against those pathogens, in generating inflammation that causes all sorts of breakage and change in cellular behavior, and in cleaning up the waste and debris produced by other cells. Amyloid-β, altered tau, and α-synuclein are all produced in some amount by normal, healthy, young people, but clearly they do not suffer for it, and nor does it build up. Any hypothesis of disease progress must account for what changes in older individuals.

An interesting point of commonality between the various forms of aggregated protein in the brain is that the largest and most obvious deposits, neurofibrillary tangles in the case of tau, are not the worst of the problem. You might think of them as the result of our biology trying to build ever bigger middens to cope with the waste that piles up. Cells dump it into the surrounding environment, or become overridden with garbage that they sequester into lumps when they can't even keep up with that. This is harmful, but as it turns out not as harmful as the surrounding halo of related biochemistry: for the most part it isn't the garbage in the middens that causes cell death and dysfunction, but rather a collection of associated proteins and their subtle interactions with cells. This is well established for amyloid-β, and the paper noted here makes an argument for this to be the case for tau as well.

Researchers describe new biology of Alzheimer's disease

Scientists have known for a long time that two proteins, β-amyloid and tau, clump and accumulate in the brains of Alzheimer patients, and this accumulation is thought to cause nerve cell injury that results in dementia. Recent work by these researchers has shown that the clumping and accumulation of tau occurs as a normal response to stress, producing RNA/protein complexes termed "stress granules," which reflect the need for the brain to produce protective proteins. The persistence of this stress response leads to excessive stress, the accumulation of pathological stress granules, and the accumulation of clumped tau, which drives nerve cell injury and produces dementia.

In the current study, the researchers use this new model and show that reducing the level of stress granule proteins yields strong protection, possibly by reducing persistent pathological stress granules as well as changing the type of tau clumping that occurs. The team hypothesized that they could delay the disease process by reducing stress granules and decreasing this persistent stress response by genetically decreasing TIA1, which is a protein that is required for stress granule formation. Reducing TIA1 improved nerve cell health and produced striking improvements in memory and life expectancy in an experimental model of AD.

Although the experimental models had better memory and longer lives, the team observed more clumped tau in the form of neurofibrillary tangles. To explain how this might be associated with a better outcome, the researchers looked at the type of tau pathology and showed that reducing TIA1 dramatically lowered the amount of tiny clumps, which are termed tau oligomers and are particularly toxic. "Reducing TIA1 shifted tau accumulation from small to large clumps, decreasing the amount of small tau clumps and producing a proportional increase in the large tau clumps that generate neurofibrillary tangles and are less toxic."

Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles.

Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

Comments

@Reason, is that a bad news? Removing amyloids was the main SENS strategy to win the AD's war. Now we have 4 systems for selective degrading proteins -- 2 specifically for amyloids and for 2 general use. Of course, we anyway need to remove neurofibrillary tangles from the brain, but we now should seek for the primary cause of AD. We need to rejuvenate our brain.

Posted by: Ariel at November 23rd, 2017 12:53 PM

@Ariel: No, this isn't bad news; it is a sign that the tau side of the research community is maturing and making progress, catching up to the point at which the amyloid side has stalled, which is the construction of working therapies to clear out aggregates. The understanding is there.

I think that the first practical results in Alzheimer's will actually come from unblocking cerebrospinal fluid drainage, as that should reduce levels of all of the aggregates without the need for complicated biotechnology. It won't be as simple as drilling holes in the skull, but probably won't be anywhere near as complicated as work on immunotherapies.

Posted by: Reason at November 23rd, 2017 1:07 PM

@Reason, thank you for your answer! I am writting a popular essay on SENS approach (firstly in Russian, then in English), hovewer, news comes so fast that I make changes every day. Now I should completely remake AD section.

Posted by: Ariel at November 23rd, 2017 2:15 PM

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