Alzheimer's progression probed

Scientists have revealed “how Alzheimer’s infects the brain”, according to The Independent. The newspaper said that research has demonstrated the “infectious properties” that allow defects in a protein “to be transmitted through the brain”, leading to the degeneration of brain function.

In the animal study behind this report, researchers investigated tau proteins. These are common structural elements in the brain. When not functioning normally, they form tangled filaments that are seen in the brains of Alzheimer’s patients. The researchers injected the brains of mice with extracts from the brains of other mice that produced defective ‘tau’ proteins. The study demonstrated that the abnormal tau properties were transferred to the brains of the injected mice and that abnormalities spread from the site of injection.

While this research is interesting, it is unclear how the findings of this animal study apply to human health. Importantly, reports on this study should not be interpreted to mean that Alzheimer’s disease or other such neurodegenerative conditions are “infectious” or contagious, as some coverage might unintentionally imply. The mechanisms of transmission uncovered in this study were in animals receiving experimental transfers of brain material and nothing in this study suggests Alzheimer’s disease or dementia can be transmitted from person to person.

Where did the story come from?

This research was conducted by Dr Florence Clavaguera and colleagues from a number of European institutions including the University of Basel in Switzerland and the Medical Research Council’s Laboratory of Molecular Biology in Cambridge.

The research was funded by the Swiss National Science Foundation, the Alzheimer’s Association, the German National Genome Network, the German Competence Network in Degenerative Dementias and the UK Medical Research Council. It was published in the peer-reviewed journal Nature Cell Biology.

What kind of scientific study was this?

This was a laboratory study in mice, which investigated the mechanisms behind the spread of the protein brain tangles characteristic of Alzheimer’s disease and certain other neurodegenerative conditions.

During disease progression, these tangles, which contain the tau protein, appear in a region of the brain called the transentorhinal cortex. From this region, these tau tangles spread to other areas of the brain, including the hippocampal formation and the neocortex. Symptoms of cognitive impairment are most prominent when tangles are in the hippocampus.

The researchers made use of types of mutant mice that had produced an abnormal version of the human tau protein. They used two different sets of mice:

• the ALZ17 line that produce long forms of the tau protein, and
• the P301S line, with a mutation that causes them to produce shorter tau protein filaments, which have been linked to inherited frontotemporal dementia.

In humans, frontotemporal dementia, or Pick’s disease, is a rare dementia characterised by changes in personality and behaviour, and usually affects people under 65. Pick’s disease is different from Alzheimer’s disease.

The researchers injected extracts from the brains of six-month-old P301S mice into the brains of three-month-old ALZ17 mice. They also injected brain extracts from the P301S mice into normal (non-mutant) mice to investigate the effect in brains where there were initially no tau protein abnormalities.

The researchers used various staining techniques to investigate the brain changes in these mice and to estimate what was happening with the tau proteins. Silver staining was used to observe tau lesions in different regions of the brain.

What were the results of the study?

Injecting the ALZ17 mice with brain extracts from P301S mice (with a mutation linked to frontotemporal dementia) resulted in transfer of tau pathology to ALZ17 mice. In other words, they showed evidence of tau filaments. These ALZ17 mice showed an increase in tau lesion concentration within the hippocampus at six, 12 and 15 months after the injection.

The silver staining that indicated the presence of tau filaments spread to regions of the brain that neighboured the injection sites. There was no obvious sign of neurodegeneration in these mice 15 months after the injection.

Injecting brain extracts from P301S mice (with a mutation linked to inherited frontotemporal dementia) into normal mice increased the presence of tau protein threads and coiled bodies, but not of tau tangles. These stayed in the injection sites and did not increase in number between six and 12 months (unlike the pattern seen in the ALZ17 mice).

What interpretations did the researchers draw from these results?

The researchers concluded that their findings demonstrate the transmission of disease caused by tau abnormalities (tauopathy) between mutant mice strains. Their methods provide an “experimental system” that can be used to investigate the way disease spreads through the brain and to further understand the effects that different types of tau protein may have.

They say that different neurodegenerative diseases are characterised by different types of tau in brain lesions and that this has some parallels with the different strains of prions (infectious proteins that affect brain structure and neurones) that can cause disease.

What does the NHS Knowledge Service make of this study?

Despite the wording of some press coverage, it should be clarified that the mechanisms uncovered in this study do not suggest that Alzheimer’s disease or other such neurodegenerative conditions are infectious, contagious or can be transmitted from person to person.

Instead, this study has demonstrated that it is possible to transmit brain pathology involving abnormal tau protein between brains of mutant mice under experimental laboratory conditions. The most immediate human relevance of this study’s findings is that they could one day contribute to understanding how neurodegenerative diseases, such as Alzheimer’s disease, progress through the brain. However, the direct application of this research to human health remains unclear.

There are several further points to keep in mind when reading the reports of this study:

• The research involved injected extracts from the brains of P301S mice with a mutation that has been linked to frontotemporal dementia. This is a distinct form of dementia and a completely separate diagnosis from Alzheimer’s disease.
• At its heart, this study has provided a way that researchers can further their understanding of the complex processes that underpin diseases caused by tau abnormalities, or tauopathies.
• Researchers note that the methods they have developed could be used to determine whether distinct types of tau proteins are responsible for different neurodegenerative conditions involving tau abnormalities. They say that this can be investigated by injecting ALZ17 mice with brain extracts from patients with these different diseases.
• The injected ALZ17 mice did not show any signs of neurodegeneration 15 months after injection. According to the researchers, this suggests that the tau proteins responsible for “transmission and neurotoxicity” are not the same.

The researchers have identified a method that will undoubtedly feature in future research into the processes behind human neurodegenerative illnesses, such as Alzheimer’s disease. As this study was carried out in mutant mice, the direct relevance to what happens in the brains of humans remains unclear.