Longevity Briefs: Why Does Tau Protein Aggregate In Alzheimer’s Disease?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Two proteins are famous for their accumulation in the brains of Alzheimer’s disease patients: amyloid beta and tau. The story of these proteins and their relationship with Alzheimer’s is complex – they may not be primary drivers of the disease as was once believed, but they certainly play a role. Both of these proteins are harmless until they fold incorrectly, which causes them to aggregate together into plaques. These plaques are insoluble, challenging to remove from the brain, and eventually grow large enough to physically disrupt and kill neurons.

Unlike amyloid beta, tau aggregates inside of neurons. But why does tau misfold and aggregate in the first place? Cells have systems for managing and maintaining the correct balance of proteins and ensuring their quality – this collection of systems is known as proteostasis. An essential part of proteostasis is the ability to break down damaged and misfolded proteins into their constituent subunits to be recycled – a process that occurs in a structure called the proteosome. Yet with advancing age, proteostasis is disrupted, leading to an increase in faulty proteins. How exactly does this happen, and why does it affect some people more than others? In this study, researchers take a closer look at how the waste disposal aspect of proteostasis fails in neurons.

The discovery:

In previous research, the authors had discovered that neurons actually have an additional type of proteosome that other cell types lack. These were dubbed neuroproteosomes. Unlike regular proteosomes, neuroproteosomes sit in the cell membrane and break down proteins before releasing the products outside of the cell. The researchers hypothesised that these neuroproteosomes might be particularly important for preventing tau aggregation. To test this theory, they first developed drugs that selectively block neuroproteosomes, preventing them from evacuating waste from the cell. Since these drugs were too large to enter the cell, they would leave the function of regular proteosomes intact.

As suspected, the researchers found that neurons exposed to these neuroproteosome blocking drugs were significantly more susceptible to tau aggregation, suggesting that these neuroprotesomes might be particularly important for preventing the accumulation of misfolded tau. Upon analysing the tau aggregates from these neurons, they found that their molecular structure was identical to that found in Alzheimers’ disease. The fact that this wasn’t some novel form of tau produced exclusively by blocking neuroproteosomes, but the same form found in Alzheimers’ indicated that this mechanism could be relevant to the disease.

To glean further insights into any potential link with Alzheimer’s disease, researchers investigated whether there was an association between neuroproteosomes and the most important genetic predictor of Alzheimer’s: ApoE gene variants. There are three major ApoE gene variants in humans (ApoE2, 3 and 4), with ApoE4 being the strongest risk factor for Alzheimer’s. The researchers found that in neurons from mice that were genetically engineered to carry the human ApoE4 variant, neuroproteosome levels in the cell membrane were significantly lower than for the other 2 variants, and it took less neuroproteosome inhibition to trigger tau aggregation. This association also existed in post-mortem human brains. Carriers of two ApoE4 variants had lower neuroproteosome levels than carriers of two ApoE3 variants, while ApoE3 carriers who died with Alzheimers disease had lower neuroproteosome levels than those who died Alzheimer’s-free. Lower levels of neuroproteosome also corresponded to brain regions more affected by the disease, showing a clear correlation between genetic risk, disease severity and neuroproteosme deficiency.

Last but not least, researchers looked at neuroproteosome levels in the neurons of mice of different ages. They found that neuroproteosome levels began to decline when the mice were around 12 moths old, suggesting that the loss of these structures is a component of ageing, not just a consequence of ApoE variants.

The implications:

This research hints at a new mechanism linking ApoE variants to tau aggregation. It seems as though ApoE regulates the number of neuroproteosomes in the cell membrane. If insufficient neuroproteosomes are present, then misfolded tau cannot be processed and expelled from the cell quickly enough to prevent aggregates from forming. The researchers proposed that ApoE variants may determine how many neuroproteosomes neurons start off with, and this number then declines with age. People with ApoE4 variants have fewer neuroproteosomes and therefore cannot afford to lose as many before pathological tau aggregation sets in.

This is not the only way in which ApoE variants contribute to Alzheimer’s disease, but it may be an important piece of the puzzle explaining how the pathology of Alzheimer’s is initiated, and how the risks associated with the ApoE4 variant might be mitigated in the future.