• Hugo Creeth

Untangling Alzheimer’s

One major factor of Alzheimer’s disease is the huge tangles of a protein known as tau protein in the brain. A new study that has just been published in the Journal of Experimental Medicine proposes an immunological mechanism that is driving this tau clumping.

Previously brain scans in humans have indicated that forgetfulness and confusion become visible soon after the tau tangles begin to fuse into a large mass. The current study focussed on a specific type of immune cell that is only found in the central nervous system (CNS), microglia. The researchers explained how microglia become active as the tau masses begin to develop. They also demonstrated how by eliminating microglia you can greatly reduce tau-related damage to brain cells of transgenic mice that are predisposed to developing tau tangles.

The two most common candidates linked to Alzheimer’s induced dementia are: tau and beta-amyloid protein. It is believed that these proteins form “plaques” as people age, however in Alzheimer's disease the rate of formation is faster and the quantity much greater. This ultimately leads to the destruction of brain tissue and subsequent cognition of those afflicted by the disease.

Multiple roles of Microglia

In the brain of healthy people, tau is a protein that plays a key role in supporting the function of neurons. The protein stabilises “microtubules”; the transport system of the neurons that ferry nutrients through the cell a bit like a train line.

It is when tau begins to act abnormally that issues arise, ultimately leading to the build ups of tau protein described. This is evident not only in those people suffering from Alzheimer’s disease, but also chronic traumatic encephalopathy (CTE). The condition that has become more prevalent in recent years after it has been reported to affect 99% of NFL players as well as at least 20% of boxers.

The link between tau protein and microglia is not new. Previous research by the team behind this study lead by Professor Holtzman, had revealed a positive relationship between microglia and tau. They showed that microglial immune cells had the ability to limit the formation of toxic tau. It was during this previous study, however, that they realised that microglia may be an example of a double edged sword. Inadvertently damaging neighbouring neurons, whilst attempting to combat the tau tangles in the late stages of Alzheimer’s disease.

The Study

Subsequently the team set to work on further characterising the Microglia-tau relationship. To do this they used genetically altered mice that were programmed to produce human tau in their brains at 6 months of age, resulting in brain damage at 9 months.

Some of the mice additionally carried a gene, APOE4, that increases the risk of Alzheimer's by 12 times, via the increased toxicity of tau.

Knowing all of this, the researchers took a subset of the mice at 6 months of age and started to supplement their diet with a compound formulated to reduce microglia in the brain. The rest were given a placebo.

At nearly 10 months of age, the researchers imaged the brains of these mice, discovering that the presence of microglia substantially increases brain shrinkage. In contrast, mice given the supplement showed hardly any brain shrinkage and very little evidence of tau toxicity.

In further experiments they revealed that the APOE gene triggers microglia activation. It is thus hypothesised that once they are activated by this risk gene they are the drivers of toxic tau tangles.

Future Hope

The study offers a new hope for combating this devastating disease. The realisation that microglia drive neurodegeneration via inflammation induced neuronal death, and that this can be nearly eradicated via a supplement is ground breaking. The compound used is unsuitable for humans. However the researchers believe that it will offer a starting point for drug discovery and development as the challenge to overcome the disease jumps forward.

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