Monthly Archives: September 2017

Watchers on the wall: Microglia and Alzheimer’s Disease

By Laura Thei, University of Reading, UK

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.

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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.

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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.

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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.

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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!

Mitochondria: the little engines that could

By Beatrice Filippi, University of Leeds, UK, & Andrew Philp, University of Birmingham, UK, @andyphilp_lab

Mitochondria, the energy producing bodies within our cells, play a pivotal role in all aspects of body function. Different pathological conditions such as Type 2 Diabetes, cardiovascular disease, neurodegenerative diseases and aging have all been associated to the loss of mitochondrial function.

As such, understanding how mitochondria are regulated in these disease states holds tremendous therapeutic potential for tackling numerous diseases of aging. Over the past two days, scientists from around the world have been discussing current topics in mitochondrial function at The Physiological Society’s sponsored ‘Mitochondria: Form and Function’ meeting in London. The meeting has focused on 4 main topics thought central in the regulation of mitochondrial function; (1) calcium signalling, (2) mitochondrial dynamics, (3) mitophagy, and (4) mitochondrial metabolism. Below is a brief summary of the topics discussed in each symposium.

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Mitochondria in lung cells

Calcium and Mitochondria 

The mitochondria can take up and release calcium depending on their cellular needs. The calcium in the mitochondria is involved in energy production. Rises in calcium in the cell also activate or inhibit different cellular events. Finally, changes in calcium levels in the mitochondria can trigger cell death. The identification of the molecules that control the mitochondria’s calcium homeostasis (i.e. the levels of calcium inside or outside the mitochondria) has been the focus of the scientific community for the last few years. This will favour the development of more targeted therapies that specifically restore the ability of the mitochondria to regulate calcium homeostasis.

Mitochondrial Dynamics 

In response to excess or lack of nutrients, mitochondria adapt their functions by changing shape and localization within the cell and increasing or decreasing in number. Fusion causes the formation of bigger and elongated mitochondria and is linked with increased energy generation. For example, insulin increases mitochondria fusion in heart muscle cells to improve mitochondrial membrane potential (the difference in ions on both sides of the membrane), elevate levels of energy in the cell, and oxygen consumption. Mitochondria fission, or separation into smaller parts, is linked with a decrease in energy production in response to energy excess. The adaptation to changes in metabolic environment, meaning energy levels, is controlled by changes in mitochondrial dynamics. Alterations in the fission/fusion mechanisms have been associated to various metabolic diseases like obesity and diabetes and neurodegenerative diseases, like Parkinson and Alzheimer’s.

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Networks of mitochondria (in blue) within cells

Mitophagy 

To maintain healthy and functional mitochondria, mitochondria undergo cyclical periods of synthesis and degradation. The process of mitochondrial degradation is termed mitophagy, and appears to be of specific functional importance in all tissues within the body. Of interest, compared to other aspects of mitochondrial regulation, such as calcium handling and dynamics, very little is known about how mitophagy is regulated and what the physiological signals are that causes mitophagy to begin in cells. One of the main limitations in the field is the ability to measure mitophagy in vivo, meaning in living cells. However, this gap in knowledge appears to have been addressed by the generation of new mouse models in which researchers can visualise when mitophagy is happening in real time. Moving forward, these tools could help shed light on how mitophagy contributes to mitochondrial control in numerous diseases of aging.

Mitochondrial Metabolism 

Mitochondria are dynamically regulated within our body and highly sensitive to changes in physiological stimuli such as exercise, inactivity and changes in diet. The focus of the final symposium was on two key factors, (1) how exercise changes mitochondrial content (the molecules inside of it) and function in skeletal muscle, and (2) how our diet affects mitochondrial function. It has been known for over 50 years that exercise increases mitochondrial content and the result is an increased oxidative capacity of the muscle (their ability to use oxygen) and greater resistance to fatigue. It also now appears that exercise changes mitochondrial dynamics in skeletal muscle, and alters the organisation of mitochondrial form and function. In contrast, ingestion of high amounts of saturated fats can lead to the development of Type 2 Diabetes, with this process appearing to occur in parallel to a reduction in mitochondrial function. Of note, this negative effect can be inherited in offspring when the mother ingests a high-fat diet, suggesting genetic imprinting, heritable changes in genes, is occurring. Therefore, strategies to maximise the exercise signal(s) or combat the negative effects of saturated fats on mitochondrial function are being explored as frontline approaches to combat numerous diseases of aging.

Tales of a Nazi-fighting Nobel Prize winner

You probably haven’t heard of AV Hill, but if you’ve ever ridden a bike, watched the football or lifted a finger, you should thank him. The introduction real-estate buffs get of AV Hill, whose Highgate home has recently gone up for sale, certainly illustrates the universal impact of physiology! The house itself sports a Blue Plaque describing A.V. simply as ‘Physiologist,’ unveiled in 2015 in the presence of The Physiological Society. David Miller, Chair of our History & Archives Committees & Hon. Res. Fellow of the University of Glasgow, UK, wrote for Physiology News about the ceremony commemorating the ‘Nazi-fighting Nobel Prize winner.’ 

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The Blue Plaque. Photo credit: David Miller

The [unveiling of AV Hill’s Blue Plaque], sponsored by Atelier and the estate agents Savills, was attended by a number of AV’s extended family, together with dozens of other guests and dignitaries. Jonathan Ashmore, Fran Ashcroft and I represented The Society. Brief speeches were made by Greg Dyke (Chairman of The Football Association and former Director General of the BBC), Dr Julie Maxton (Executive Director, Royal Society), Prof Nicholas Humphrey (psychologist and philosopher), Stephen Wordsworth (CARA – Council for Assisting Refugee Academics) and Sir Ralph Kohn FRS (founder of the Kohn Foundation) who had proposed the Blue Plaque to honour AV’s memory.  Amongst the speeches, Nicholas Humphrey (a grandson of AV) described that regular guests at the house included many Nobel laureates, AV’s brother-in-law, the economist John Maynard Keynes, and friends as varied as Stephen Hawking and Sigmund Freud. The afterdinner conversations involved passionate debates about science and politics. ‘Every Sunday [as a child] we would have to attend a tea party at grandpa’s house and apart from entertaining some extraordinary guests, he would devise some great games for us, such as frog racing in the garden or looking through the lens of a [dissected] sheep’s eye.

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AV Hill in 1955. Photo credit: Harold Lewis

Archibald Vivian Hill (1886-1977)–known to all as ‘AV’–was the first British winner of the Nobel Prize for Physiology or Medicine (in 1922/3), honoured for his early work on heat production in muscle. He is widely regarded as a founder of the discipline of biophysics, bringing his command of mathematics and physical principles to his work in physiology.  His research work was fundamental in areas as varied as hormone-, neurotransmitter- and drug-receptor physiology, enzyme kinetics, muscle metabolism, nerve function, the mechanism of muscle mechanical function and more. One reason for the speech from Greg Dyke, representing the FA at the unveiling, is that aspects of AV’s work are also recognised as foundations of Sports Science: AV was himself a gifted athlete. He was mentor to several generations of leading physiologists. He led the physiology department at Manchester University (1920-23) and then at University College London (1923-1951). He joined The Society in 1912 and filled many major roles (Secretary 1927-33, Foreign Secretary 1934-45, served many years on the Editorial Board of The Journal of Physiology). He was elected a Fellow of The Royal Society in 1918, going on to fill several senior roles (Council from 1932-4, Biological Secretary 1935-45, Foreign Secretary 1946) and held a Royal Society Foulerton Professorship. In World War II, he served as the (independent) MP for Cambridge University, his alma mater, and on government wartime science and technical committees.

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A.V. Hill’s Nobel Prize certificate

Beyond his research, mentoring, government work, science administration and teaching, AV’s humanitarian work was exemplary. He played a leading role in setting up CARA (in 1933, with Ernest Rutherford, William Beveridge and others) and thus in the work to assist and support scientists escaping persecution in Nazi Germany. At the Blue Plaque ceremony, Sir Ralph Kohn referred to this endeavour: whilst still a child, Sir Ralph himself had escaped (together with his parents) from Leipzig in 1935. Sir Ralph reminded me that Bernard Katz had also escaped Leipzig the same year. He became a PhD student of AV and lived for some years as a lodger at AV’s home: thus there is a case for a further physiologist’s Blue Plaque at 16 Bishopswood Road.

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The unveiling of the Blue Plaque, September 2015. Credit: David Miller

Hill said and wrote much that is worthy of being quoted. As a champion of the value of unfettered original research, he observed in his Inaugural Lecture for the Jodrell Chair of Physiology at UCL in 1923 (when he succeeded Ernest Starling), ‘Medicine is continually demanding more information and help in the grievous and urgent problems which it has to solve – useful information, practical information, information which is likely to help heal … minds and bodies. It is impossible not to be moved by this appeal, and in their hearts there are few physiologists who do not hope that their work may prove, in some sense and at some good time, of service to mankind in the maintenance of health, in the prevention of disease, and in the art of science and healing. One’s heart, however, is not always one’s best guide; more useful in the end is the intellectual faith … which urges Tom, Dick and Harry in their humble way to explore each his own little strange and miraculous phenomenon, whether in the organic or inorganic world.’ [as quoted by Brian Jewell in Physiology News, Summer 2008, p12].