Having recently written two recent pieces on the flu virus it was interesting to read this week that horse racing has been suspended in the UK due to equine flu caused a sub type of influenza type A (H3N8). This has resulted in a six-day suspension in the racing calendar with 174 stables in the UK shut down after three cases of equine flu were discovered in Cheshire.
This week I have decided to write a piece on a very different subject.
Dementia is not a single disease but rather a term to describe several illnesses that predominantly affects people over the age of 65. Alzheimer’s accounts for over 60-80% of all dementia cases. Present estimates suggest that there are about 850,000 cases in the UK, although with the current population age profile, this will rise to two million by 2051.The Medical Research Council website states “there is currently no cure for any of the neuro-degenerative conditions that give rise to dementia, this represents one of the toughest medical and economic challenges facing our society today”.
To understand Alzheimer’s, we need to first understand a little about our central nervous system. A typical healthy human brain has roughly 100 billion neurons! In fact, up to 20% of the energy we produce services our brain function. Clearly neurons are specialised cells in our brain that transmit and receive signals using chemical and electrical pathways. Most cells in the human body live for a relatively short amount of time, but neurons can live up to 100 years. As a result of this longevity they undergo constant repair, maintenance and regeneration so we maintain our memory and can learn. Overall the most common cell in the brain are glial cells such as oligodendrocytes, astrocytes and microglial cells. In fact, there are about ten times more glial cells than neurons. The glial cells help support the neurons and have a close interaction with blood vessels in order maintain the function and well-being of each neuron. Microglial cells for instance help protect neurons from any physical or chemical damage. The maintenance of all neurological pathways is essential for our sense of self, memory recall and homeostatic function. The problem with Alzheimer’s is that these pathways break down.
Neurons have three essential components, a cell body, dendrites and axons. Obviously, the cell body comprises the cell nucleus, genetic material and regulates internal cell function. The dendrites meanwhile extend from the cell like branches from a tree and gather information from other neurons and receive incoming messages. The axons are long cable-like structures that extend from the opposite end of the cell from the dendrites. They send messages to other neurons and conduct outbound information.
As soon as the neuron receives a signal from another neuron it transmits an electrical charge sending the message down the axon which then eventually reaches a tiny gap called a synapse. Here the signal is transmitted via a neurotransmitter across the gap which binds onto a receptor site at the other side of the synapse. One the other side of the synapse is a dendrite of a nearby neuron which propagates the message. One neuron may have up to 7000 synaptic connections with other neurons. Synaptic connections evolve and change throughout our lives depending on how much stimulation they receive. New connections maybe destroyed or generated through our lifetime.
So, what happens when we have Alzheimer’s? We now understand that tiny bundles of protein plaque begin to form. These plaques progressively inhibit function both within and outside a neuron cell body (although different mechanisms are involved).
One of the most important structures inside a cell body are microtubules. Microtubules are microscopic hollow tubes that are part of a cell’s cytoskeleton, a network of protein filaments that extends throughout each cell. They give the cell shape, help keep all the vital components in place and act as tiny little railway tracks. They are like an inner transport network enabling essential materials to move within a cell. A Tau protein is a vital part of a microtubule structure. Two major known functions of Tau are its ability to promote assembly and to maintain structure of microtubules. In Alzheimer’s, because of abnormal chemical changes, small fragments of Tau aggregate together abnormally creating Tau tangles which then join one another forming ever larger aggregates. These tangles block the transportation network inside the cell, eventually affect cell communication and cause cell death.
Another issue in Alzheimer’s is beta-amyloid protein which aggregates in between neurons forming large plaques. This a breakdown product of a larger protein called amyloid precursor protein (or APP). Although scientists have not yet determined APP’s complete function, some things are known. APP moves from the inside of neuron cell bodies to the outside by passing through the fatty membrane around the cell. When APP is stimulated to do its normal job, it is cut by other proteins into separate, smaller sections that stay inside and outside cells so they can proceed to undertake their normal roles. There are several different ways APP can be cut; under some circumstances, one of the pieces produced is beta-amyloid. Beta-amyloid is chemically “stickier” and it appears to accumulate into amyloid plaques that we view as a hallmark of Alzheimer’s. The tiny pieces first form small clusters, then chains of clusters called fibrils, then “mats” of fibrils called beta-sheets. The final stage is plaques, which contain clumps of beta-sheets and other substances. According to the amyloid hypothesis, these stages of beta-amyloid aggregation disrupt cell-to-cell communication and activate immune cells. These immune cells trigger inflammation. Ultimately, the brain cells are destroyed.
As Alzheimer’s disease progresses the volume of brain tissue decreases. In the early stages short-term memory begins to decline as the cells in the hippocampus degenerate. The hippocampus is a small organ that is an important part of our limbic system, the region that regulates emotions. The hippocampus is associated mainly with memory, especially long-term memory. The organ also plays an important role in spatial awareness. In Alzheimer’s disease, the hippocampus appears to be the first point of deterioration, leading to confusion and loss of memory. The disease will then progress throughout the cerebral cortex affecting communication, emotional behaviour and ability to rationalise. Eventually motor function will be impaired, and memory will be virtually non-existent. On average, those with Alzheimer’s live for 8 to 10 years after diagnosis, but this terminal disease can last for as long as 20 years.
The threat of Alzheimer’s is considered so important that there has been a strong government initiative to promote research and understanding. The Prime Minister’s challenge on dementia 2020 sets out more than 50 specific commitments that together will make England the world-leader in dementia care, research and awareness by 2020.
As part of this initiative the government has set up 6 dementia research institutes (DRI) in the UK one of which is at Cardiff University. At Cardiff they are undertaking research to explore different theories in Alzheimer’s backed by genetics and the role of our immune system. Professor Williams at the Institute comments “Our immune response is about how the brain keeps us safe, it’s about getting rid of things which might invade the brain, getting rid of nerve cells and bits that go wrong,”
This theory involves looking at pruning function. Pruning function is quite normal and helps our brains develop as we grow by discarding pieces we don’t require. Increasingly it is believed that this is triggered again in some people as they get older. Researchers will also look at how factors such as lifestyle and exercise could play a part.
Cardiff University also has some unique facilities such as its new £44m brain imaging research centre (Cubric) which will also be used in the project. It includes Europe’s most powerful brain scanner – which has been described as the “Hubble telescope of neuroscience”. One of the research laboratories at the DRI in Cardiff is the fruit fly research institute. It may sound a bit odd, but fruit flies share many of the same genes we do even though it’s brain only has 100,000 neurons (whereas we have 100 billion). The life cycle of a fruit fly is only a few months so aged related changes can be tracked very quickly and this in turn helps understand brain function. Dr Owen Peters, one of the research team comments “If we find a gene in the human genetic studies that looks like it’s linked to Alzheimer’s disease – and flies have it – it allows us to have a very rapid, inexpensive system, which we can test to see how these affect brain function.“