Watchers on the wall: Microglia and Alzheimer’s Disease

By Laura Thei, University of Reading, UK

Reproduced with permission from The Physiological Society’s blog.

The watch, worn by years of use, sits ticking on our table for the first time in two years. It has a simple ivory face and is the last memorabilia my partner has from Grandad Percy. Percy passed from us after a long personal battle with dementia, specifically Alzheimer’s disease. It is in his name that my partner and I will take to the beautiful winding pathways beside the Thames, to raise money for the Alzheimer’s Society.

We will be taking part in a 7 km Memory Walk, with thousands of others, some my colleagues from the University, each sponsored generously by friends and families, each who has had their life touched by this disease in some way. Last year nearly 80,000 people took part in 31 walks, raising a record £6.6 million. As a researcher in Alzheimer’s disease, I am acutely aware of every penny’s impact in helping to solve the riddle of dementia. 

Alzheimer’s Society Memory Walk

Alzheimer’s disease is ridiculously complicated. Oh, the premise is simple enough: two proteins, amyloid beta and phosphorylated tau, become overproduced in the brain and start to clog up the cells like hair down a plug. This causes these cells to be deprived of nutrients, oxygen and other vital factors that keep them alive. This eventually causes regional loss in areas specific to memory and personality. It’s simple in theory, but the reality is that we still have much to learn.

Current, extensive research is starting to answer these questions and whilst there is a growing list of risk factors – genetic (APOE4, clusterin, presenilin 1 and 2) and environmental (age, exercise, blood pressure) – confirmation only occurs when a brain scan shows the loss of brain region volume in addition to the presence of amyloid beta and tau. This means that by the time someone knows they have the disease, it’s possible that it’s already been chugging away at their brains for some time.

So we need to push diagnoses earlier. To do that we need to look at the very early stages of the disease, down to a cellular level, to find out how we can prevent the build-up of amyloid and tau in the first place. This is what I, the group I’m in, and many other researchers nationally and globally are striving to do.

In a non-active state, microglia lie quietly surveying their local area of the brain. ©HBO

I am specifically focusing on the immune cells of the brain, microglia, and their contribution. Microglia are the most numerous cells in the brain. They act as the first line of defence, so their involvement and activation is often seen as an early sign of disease progression. Like all good defences, they tend to be alerted to damage before it becomes deadly. But, like the neurons (the basic building blocks of the brain), microglia are also susceptible to the disease. If they die, does that leave the brain more vulnerable to further insult? That is what I would like to know too!

In a non-active state, microglia lie quietly surveying their local area of the brain. When activated by a threat to the brain, they cluster around the targeted area, changing shape in the process. They then enter one of two states. The pro-inflammatory state releases molecules that attack the harmful pathogens directly, and the anti-inflammatory state releases ones that promote healing and protection of the area.

Microglia can change shape to either attack pathogens or protect the area. ©Nickelodeon

With Alzheimer’s, microglia are activated by the accumulation of amyloid, not damage. They absorb the amyloid beta, and in the process, trigger the pro-inflammatory response. This then increases the permeability of the brain’s blood supply, allowing immune cells into the brain to assist removal of the excess protein. However, in the brain of Alzheimer’s patients, the amyloid beta production outdoes the microglia’s ability to remove it. This creates a perpetual cycle of pro-inflammatory response, releasing molecules that can kill cells in the brain. It is unclear whether there is a threshold between beneficial or detrimental in the microglial response.

Microglial response to fight Alzheimer’s Disease can become detrimental. ©2011 Scott Maynard

Given the importance of microglia in neurodegenerative diseases, a new field of microglial therapeutics has recently emerged, ranging from pharmacologically manipulating existing microglia by switching their response status, to inhibiting microglial activation altogether. Continued research and clinical efforts in the future will help us to improve our understanding of microglial physiology and their roles in neurological diseases.

We’re making progress, but there’s still a long way to go, which is why every penny counts!

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