Introduction

ROBERTA WARD, DAVID DEXTER AND ROBERT CRICHTON

1.1 Outline

The complexity of the human brain is staggering, able to coordinate the fingers, hands and feet of an organist, all playing on three different keyboards, and to create three-dimensional images from light falling on a two-dimensional retina. While the brain regulates all aspects of the functions of our bodies, in our post-genomic era we are still a long way from understanding it, despite the enormous strides made in DNA sequencing. Weighing only about 1.4 kg (only 2% of body mass), the brain accounts for 20% of our total oxygen consumption and 25% of our glucose utilisation. However, as the human population lives longer and longer, hand in hand with our ever-increasing life expectancy goes an alarming increase in the incidence of neurodegenerative disorders, affecting both cognititive and motor function. Neurodegenerative disorders are set to overtake cancer to become the second most common cause of death by 2040. The most common of these are dementias, the characteristic of which is decline in cognitive faculties and occurrence of behavioural abnormalities which interfere with the capacity of the afflicted individual to carry out normal daily activities. It usually affects elderly individuals and occurs in many different forms, of which the most common is Alzheimer's disease (AD). In the World Alzheimer Report 2009, Alzheimer's Disease International (ADI) estimated that 36 million people worldwide are living with dementia, with numbers doubling every 20 years to reach 66 million by 2030, and 115 million by 2050. Dementia prevalence increases with age; in the USA, whereas 5.0% of those aged 71-79 years are affected, this climbs to 37.4% of those aged 90 and older. Dementias are chronic, progressive, long-lasting and, so far, incurable diseases, the worldwide costs of which now represent more than 1% of global GDP. In other words, if dementia care were a country, it would represent the world's 18th largest economy. 3Of the neurodegenerative diseases affecting motor function, Parkinson's disease is the most common, and it is estimated that 6.3 million people worldwide suffer from the disease. It is the second most prevalent neurodegenerative disorder, affecting 1% of those over 60, and 4% of those over 80.

1.2 Interplay Between the Peripheral Circulation and Brain: Importance of the Blood–Brain Barrier

The brain contains about 10 specialized nerve cells, called neurons, which send electrical impulses at high speeds over long distances, down their axons. Each neuron can interconnect with tens of thousands of other neurons, at junctions called synapses. The human brain contains more than 10 of these synaptic connections, which forge enormously complex neural circuits, undergoing continuous remodelling. The brain also contains cells of a different type, called glial cells, which account for 90% of the brain's cells and more than half of its volume. An accumulating body of work over the last two decades has revealed that the glial cells are important regulators of synaptic connectivity, involved in the control of synapse formation, function, plasticity and elimination, both in health and disease. Figure 1.1 presents a representation of neurons and the three main types of glial cells.

There are three types of neurons: multipolar neurons, motor neurons and sensory neurons. Some collect information about our environment (both external and internal), which they transmit to other neurons, where the data are either processed or stored, while others respond to this information to regulate the control of muscle contraction, hormone synthesis, etc. Sensory neurons collect all sorts of information, concerning light, smell, sound, pressure, touch, etc., through specialized receptors, and transform this information into electrical signals, whereas multipolar neurons receive synaptic signals from several hundred other neurons and transmit them to many other neurons at the lateral branches of their terminals. Motor neurons transmit nerve impulses to muscle cells, and their single, often very long, axons extend from the cell body of the neuron to the effector muscle cell. They have an insulating sheath of myelin, a kind of biological insulating tape, covering all parts of the axon except for the nodes of Ranvier and the axon terminals at the neuromuscular synapse. This allows them to propagate nerve impulses at velocities of up to 100 m s-1, around ten times faster than in unmyelinated nerves.

There are three principal types of glial cells, namely astrocytes, oligod-endrocytes and microglia. Astrocytes are star-shaped glial cells which are the major cell type in the central nervous system (CNS). The network of astrocytic processes forms the infrastructure on which all other CNS cells and vessels are anchored. They have a multitude of functions, including regulation of the ionic milieu in the intercellular space, uptake and/or breakdown of some neur-otransmitters, supplying nutrients to the neurons and formation of the blood–brain barrier (BBB). Astrocytes also produce and secrete substances that have a major influence on the formation and elimination of synapses.

Oligodendrocytes are involved in the electrical insulation of nerve fibres (axons), wrapping up to 150 layers of myelin sheath approximately 1 µm thick around the axons of neurons, rather like electrical insulating tape. One oligodendrocyte can extend its processes to up to 50 neuronal axons. In the peripheral nervous system the function of the oligodendrocytes is replaced by Schwann cells, which however can wrap around only one axon. High numbers of proliferating oligodentroglial progenitor cells are present to ensure remyelination can occur when necessary. New studies of human brain using magnetic resonance imaging (MRI) have demonstrated that myelinating oligodendrocytes sense electrical activity in axons, revealing that white matter changes after learning complex tasks.

Microglia are also found in the vicinity of the BBB. The microglia are the resident macrophages of the central nervous system, which can communicate with the astrocytes and neurons and with cells of the immune system by a large number of signalling pathways. They are the most susceptible sensors of brain pathology, and when they detect any signs of brain lesions or nervous system dysfunction, they undergo a complex, multistage activation process that converts them into "activated microglia". Activated microglial cells have the capacity to release a large number of substances that can act detrimentally or beneficially...