Tau Proteins in Mice Copy Alzheimer’s and CBD Misfolds

Prions rank among nature’s most cruel tricks.

Proteins consist of amino-acid chains that must adopt highly precise folds, a process that does not invariably go to plan. The body is generally adept at fixing such mistakes, but occasionally a prion appears.

A prion is not merely a misshapen, useless protein. It has a distorted form that carries the instructions for producing that same form, while evading the body’s disposal systems. As those instructions move through the brain, they cause swift, worsening degeneration and eventually death.

For many years, researchers have identified unsettling parallels between prion diseases and numerous neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and corticobasal degeneration (CBD).

Each involves proteins folding incorrectly. Increasing evidence also indicates that, as with prions, the misfolded proteins linked to these illnesses can trigger other proteins to misfold and clump together, enabling the pathology to travel through the brain.

Yet a vital part of the picture remained absent.

There had been no direct proof that the malformed tau proteins implicated in diseases including Alzheimer’s transmitted the blueprint of their own particular harmful architecture.

Researchers led by structural biologist Sjors Scheres and neuroscientist Michel Goedert at the UK’s MRC Laboratory of Molecular Biology have now found that evidence.

They introduced human tau proteins from people with Alzheimer’s disease and CBD into mice, then found that the animals’ own tau proteins reproduced the implanted misfolds.

How prion-like protein seeding works

A protein’s shape is fundamental to the job it can perform. It is rather like a cog in a machine: if one tooth on a cog is damaged, it might not fit into or rotate within the machine as it ought to.

What makes prions especially insidious is that they are not simply damaged cogs. They are damaged cogs that transfer their damage to other cogs, which in turn pass it to more cogs: a chain reaction that spreads through healthy tissue and leaves malfunction behind it.

Known as templated seeding, this process can vary according to the shape of the misfolded protein. Different shapes may act differently, creating what scientists term strains: separate protein architectures associated with distinct disease patterns.

Tau is not ordinarily harmful. This protein is plentiful in neurons, where it provides structural support, helps transport nutrients, and contributes to converting short-term memories into long-term memories.

However, tau can sometimes malfunction. In more than 20 neurodegenerative illnesses collectively called tauopathies, it forms abnormal filaments.

Just as distinct prion strains are linked with different prion illnesses, including bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, these filaments are not all distorted in identical ways.

Different tauopathies correspond with different tau misfolds. Alzheimer’s disease, for example, has characteristic structures, whereas CBD has a different one.

Alzheimer’s and CBD tau in ordinary mice

Earlier experiments established that abnormal tau can induce healthy tau to misfold. They also showed that abnormal tau from people with different tauopathies can create different damage patterns in animal brains.

That appeared strongly prion-like. However, scientists still could not determine whether the newly misfolded tau truly replicated the molecular architecture of the introduced tau that began the chain reaction, or whether those different architectures explained the differing disease patterns.

This was the question Scheres and his colleagues set out to answer.

They isolated misfolded tau from brain tissue generously donated for research by people who had died with Alzheimer’s disease or CBD, then injected it into the brains of living wild-type mice.

This was an important distinction, since tau-pathology research often relies on mice genetically modified to produce human tau or otherwise make the disease easier to replicate. These animals possessed only their normal mouse tau.

The team then looked after, monitored, and tested the mice carefully for several months.

After one week, human tau could no longer be detected in the mice’s brains.

Over the ensuing weeks and months, however, the animals’ own tau began to crumple. The process did not unfold identically in the Alzheimer’s and CBD groups.

Among mice given Alzheimer’s tau, misfolded mouse tau built up solely in neurons.

In mice that received CBD tau, it accumulated in neurons as well as supportive glial cells, forming structures similar to those observed in the brains of people with CBD.

Tau folds retain the human disease pattern

The researchers then examined the misfolded mouse tau at atomic resolution with cryo-electron microscopy, allowing them to identify precisely how the proteins had folded relative to the original human protein.

The similarity was remarkable.

In mice injected with Alzheimer’s tau, mouse tau adopted the same structure found in human Alzheimer’s disease. In contrast, mice injected with CBD tau developed mouse tau with the structure seen in human CBD.

The initial human tau had vanished long before, yet its imprint remained in every distorted section of the misfolded mouse tau.

The differing molecular architectures also corresponded with different pathological patterns: the Alzheimer’s fold matched the neuron-only pattern, while the CBD fold matched the characteristic combination of neuronal and glial inclusions.

Notably, the mice seemed healthy despite building up these abnormal tau structures.

It remains uncertain whether symptoms did not emerge because the animals did not live long enough, because too little abnormal tau accumulated to cause symptoms, or because the spread of misfolded tau and the harm it eventually produces represent separate disease stages.

It is also vital to stress that this does not make the tauopathies concerned directly equivalent to prion diseases. A defining feature of prion diseases is infectiousness. Tauopathies such as Alzheimer’s disease and CBD are not known to spread naturally between people.

The team now aims to disentangle the molecular mechanisms controlling how cells absorb tau seeds, how these seeds convert other tau proteins, and how they move through the brain.

Their findings indicate that ordinary mice could be a valuable model for this work.

By establishing what drives the process, the researchers hope to gain a clearer understanding of how distinct tau strains generate their characteristic disease patterns. This knowledge could ultimately help identify new approaches to diagnosing and treating these conditions.

The research was published in Nature.

This article was fact-checked and edited by Rebecca Dyer. Although we take pride in our process, we are only human. If you notice an error, please let us know.