Neural Cell Number

The adult human brain contains approximately 1012 neurons and 10 to 15 times that number of glial cells. Each neuron has, on average, 10,000 connections (from a few thousand to over 100,000), resulting in an extraordinarily large total number (about 1015). It is through these connections that the nervous system exerts its essential role in directly communicating with the internal and external environment, and, as an intermediary, between the two environments. CNS cells include neurons, and glial and endothelial cells (Box 2).

Aging affects nervous structures differentially. One striking example of this diversity involves neuronal loss. In the brain of old persons without apparent functional or pathologic deficits, loss of neurons is limited to discrete areas and shows considerable individual variability (35). In some areas of the cerebral cortex and in the cerebellum, the number of neurons remains essentially unchanged throughout life, except perhaps at very old ages (36). Other areas where losses may occur are the locus ceruleus (catecholaminergic neurons), the substantia nigra (dopaminergic neurons), the nucleus basalis of Meynert, and the hippocampus (cholinergic neurons). In all brain areas, neuronal loss appears modest compared to the redundancy of existing neurons.

Although new neurons actually continue to form in some areas of the brain in adult primates (37), neuronal loss may become quite severe in some aging-associated diseases, as for example, the marked loss of cholinergic neurons in the frontal cortex, nucleus basalis of Meynert, and hippocampus in about half of patients with Alzheimer's disease (AD) (38) and of dopaminergic neurons in the substantia nigra in patients with PD (39).

FIGURE 3 Magnetic resonance images from two normal older individuals, one not demonstrating significant cortical atrophy and one demonstrating mild cortical atrophy. A third image is from a patient with Alzheimer's disease, demonstrating severe cortical atrophy. The cortical atrophy is seen in the topmost images that display the brain surface. In addition, the hippocampus (black arrow/) in all three individuals, as seen on the image slices in a coronal plane, shows varying degrees of atrophy that generally parallel the atrophy of the cortex. Likewise, note that the ventricles are significantly enlarged (white arrows) in both mild and severe atrophy in comparison to the individual with no atrophy. Source: Courtesy of Dr. W. J. Jagust.

FIGURE 3 Magnetic resonance images from two normal older individuals, one not demonstrating significant cortical atrophy and one demonstrating mild cortical atrophy. A third image is from a patient with Alzheimer's disease, demonstrating severe cortical atrophy. The cortical atrophy is seen in the topmost images that display the brain surface. In addition, the hippocampus (black arrow/) in all three individuals, as seen on the image slices in a coronal plane, shows varying degrees of atrophy that generally parallel the atrophy of the cortex. Likewise, note that the ventricles are significantly enlarged (white arrows) in both mild and severe atrophy in comparison to the individual with no atrophy. Source: Courtesy of Dr. W. J. Jagust.

Neuronal number in experimental animals decreases slightly with aging, depending on the area considered, the type of cell, and the animal species. For example, in the cerebral cortex of rats, the number of neurons remains unchanged with age (33). Reduced numbers of neurons have been reported in discrete brain areas of aged monkeys, guinea pigs, and mice (18,34). When the number of neurons is examined in these animals at progressive ages throughout their life spans, a major reduction in cell number often occurs at young rather than old ages.

In contrast to the possible loss of neurons, the number of glial cells increases with aging in most areas, and this increase, or gliosis, involves primarily the neuroglial cells (of the same embryonic ectodermic origin as the neurons, Box 2). Gliosis is a

BOX 2 Cells of the Central Nervous System: Changes with Aging

Neurons are regarded as the primary functional cells even though the glial cells are more numerous. Dendrites and axons are cell processes branching from neurons and conducting impulses to or from the cell body. Communication between neurons is through synapses and synaptic spines (the latter, small knobs projecting from dendrites). Synapses are composed of the presynaptic membrane (often enlarged to form terminal buttons or knobs), a cleft, and a postsynaptic membrane. Present in the spines are vesicles or granules containing the synaptic transmitters synthesized in the cell. The axons may be surrounded by a specialized membrane, myelin, or may be unmyelinated. The myelinated fibers transmit the nerve impulse more rapidly than do the unmyelinated ones.

While most neurons do not divide in the adult brain, some do: the neurons that are capable of regeneration are located in the olfactory bulb and hippocampus. Additionally, the ependymal cells located in proximity to the central ventricles have the capacity to transform into multipotent cells, capable of generating neurons. Also, neuroglial cells, particularly astrocytes, classically considered part of a committed astroglial lineage, can de-differentiate into neuroblasts.

The glial cells comprise the neuroglia, of ectodermal origin like neurons, and the microglia, of mesodermal origin, and part of the immune system. Both neuroglial and microglial cells continue to divide throughout life. Neuroglial cells, long shunned as the mere "glue" of the central nervous system (CNS), as their Greek etymology implies, in fact play critical roles in brain plasticity by modulating neuronal transmission and regeneration. These cells may assume a neuronal precursor role in addition to their support of neurotransmission and metabolism (astrocytes) and myelination (oligodendrocytes). Microglial cells play a defensive role in CNS phagocytosis and inflammatory responses.

Endothelial cells of cerebral capillaries, in contrast to those in other tissues, form tight junctions that do not permit the passage of substances through the junctions. Cerebral capillaries are enveloped by the end-feet of astrocytes, a special feature that hinders the exchanges across capillary walls between plasma and interstitial fluid. The resulting, so-called blood-brain barrier prevents the entry of endogenous metabolites and exogenous toxins and drugs of the blood into the brain, and reciprocally, the entry of the neurotransmitters into the general circulation.

normal response to neuronal damage at all ages and may represent a compensatory response not only to the modest neuronal loss, but also to the neuronal, metabolic, and functional impairment (33). Gliosis persists in old age and is considered to be part of a repertory of compensatory responses that protect neuronal function and plasticity. The number of microglia cells (part of the immune system) remains essentially unchanged, except in the presence of inflammation, when the cell number increases (33).

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