Disease Protein Normal Structure Aggregate/Inclusion Location

Chapter 28 - The Central Nervous System

Matthew P. Frosch MD, PhD

Douglas C. Anthony MD, PhD

Umberto De Girolami MD

The human central nervous system (CNS) is an enormously complex tissue serving the organism as a processing center linking information between the outside world and the body. The

principal functional unit of the CNS is the neuron; the best estimates are that there are about 1011 neurons in the human brain. Neurons, although similar in many ways to other cells in

the body, are unique in their ability to receive, store, and transmit information. Neurons differ greatly from one another in many important properties: their functional roles (e.g., sensory,

motor, autonomic), the distribution of

their connections, the neurotransmitters they use for synaptic transmission, their metabolic requirements, and their levels of electrical activity at a given moment. A set of neurons, not

necessarily clustered together in a region of the brain, may thus be singled out for destruction in a pathologic condition—selective vulnerability—because it shares one or more of these

properties. Furthermore, and of particular importance in medicine, most mature neurons are postmitotic cells that are incapable of cell division, so destruction of even a small number of

neurons responsible for a specific function may leave the patient with a severe clinical neurologic deficit. Stem cell populations have been described in several areas of the brain and

represent a potential mechanism for repair after injury.[1] In comparison to other organ systems of the body, the nervous system has several unique anatomic and physiologic

characteristics: the protective bony enclosure of the skull and spinal column that contains it, a specialized system of autoregulation of cerebral blood flow, metabolic substrate

requirements, the absence of a conventional lymphatic system, a special cerebrospinal fluid (CSF) circulation, limited immunologic surveillance, and distinctive responses to injury and

wound healing. As a result of these special characteristics, the CNS is vulnerable to unique pathologic processes, and the reactions of CNS tissue to injury differ considerably from those

encountered elsewhere.[2] [3]

Normal Cells

The principal cells of the CNS are neurons, glia, and the cells that compose the meninges and blood vessels.

Neurons

In the CNS, neurons are topographically organized either as aggregates (nuclei, ganglia) or as elongated columns or layers (such as the intermediolateral gray column of the spinal cord

or the six-layered cerebral cortex).[4] Functional domains are located in many of these anatomically defined regions (such as the hypoglossal nucleus of the medulla for motor fibers of

the twelfth cranial nerve; calcarine cortex of the occipital lobe for primary visual cortex). In addition, as a further dimension of anatomic-functional specificity, some cortical and

subcortical neurons and their projections are arranged somatotopically (such as motor and sensory homunculi).[5] Neurons vary considerably in structure and size throughout the nervous

system and within a given brain region. With conventional histologic preparations, an anterior horn neuron in the spinal cord has a cell body (perikaryon) that is about 50 μm wide, a

relatively large and somewhat eccentrically placed nucleus, a prominent nucleolus, and abundant Nissl substance; the nucleus of a granule cell neuron of the cerebellar cortex is about 10

μm across, and its perikaryon and nucleolus are not readily visible by light microscopy. Electron microscopic study reveals further variability among neurons in cytoplasmic content and

the shape of the cells and their processes.[6] Characteristic ultrastructural features common to many neurons include microtubules, neurofilaments, prominent Golgi apparatus and rough

endoplasmic reticulum, and synaptic specializations. Despite these shared structures, axon length may vary greatly (hundreds of microns for interneurons versus a meter for an upper

motor neuron). Immunohistochemical markers for neurons and their processes commonly used in diagnostic work include neurofilament protein, NeuN, and synaptophysin.[7]

Glia

Glial cells are derived from neuroectoderm (macroglia: astrocytes, oligodendrocytes, ependyma) or from bone marrow (microglia). Glial cells have important structural and metabolic

interactions with neurons and their dendritic and axonal processes; they also have a primary role in a wide range of normal functions and reactions to injury, including inflammation,

repair, fluid balance, and energy metabolism. The size and shape of the nucleus helps in the light microscopic distinction of one glial cell type from another, as their cytoplasmic

processes are often not apparent on H&E preparations and can be demonstrated only with the use of metallic impregnation, immunohistochemical, or electron microscopic methods.

Astrocytes typically have round to oval nuclei (10 μm wide) with evenly dispersed, pale chromatin; oligodendrocytes have a denser, more homogeneous chromatin in a rounder and

smaller nucleus (8 μm); and microglia have an elongated, irregularly shaped nucleus (5 to 10 μm) with clumped chromatin. Ependymal cells, on the other hand, do have visible

cytoplasm; seen with H & E, they are columnar epithelial-like cells with a ciliated/microvillous border facing the ventricular surface with pale, vesiculated nuclei (each about 8 μm)

located at the abluminal end of the cell.

ASTROCYTES

This glial cell is found throughout the CNS in both gray and white matter. Protoplasmic astrocytes occur mainly in the gray matter; fibrous astrocytes occur in white and gray matter.

The cell derives its name from its star-shaped appearance, which is imparted by the multipolar, branching cytoplasmic processes that emanate from the cell body containing the

characteristic cytoplasmic intermediate filament protein called glial fibrillary acidic protein (GFAP). These are seen well in tissue sections only with metallic impregnation techniques (e.

g., the Golgi method) ( Fig. 28-1A ) or immunohistochemical preparations ( Fig. 28-1B ). The filaments are either aggregated in fascicles (in protoplasmic astrocytes) or dispersed

diffusely throughout the cytoplasm (in fibrous astrocytes). Some astrocytic processes are directed toward neurons and their processes and synapses, where they are believed to act as

metabolic buffers or detoxifiers, suppliers of nutrients, and electrical insulators. Others surround capillaries or extend to the subpial and subependymal zones, where they contribute to

barrier functions controlling the flow of macromolecules between the blood, the CSF, and the brain. Astrocytes are also the principal cells responsible for repair and scar formation in the

brain. Fibroblasts, which have a major role in wound healing elsewhere, are located mainly around large CNS blood vessels and in the meninges; they participate in wound healing only

to a limited extent (primarily in the organization of subdural hematomas and the formation of abscess cavities).

Figure 28-1 A, Astrocytes and their processes. Some processes extend toward blood vessels (Golgi). B, Immunoperoxidase staining for glial fibrillary acidic protein shows astrocytic

perinuclear cytoplasm and well-developed processes (brown). (Courtesy of Dr. J. Corbo, Brigham and Women's Hospital, Boston, MA.)

TABLE 28-1-- Neurodegenerative Diseases Associated with Aggregated Proteins

Disease Protein Normal Structure Aggregate/Inclusion Location

Transmissible spongiform encephalopathies

(Prion disease) (see Fig. 28-31 )

Prion protein (PrP) a-Helix and random coil b-pleated sheet, proteinase K-resistant Extracellular

Alzheimer disease (see Fig. 28-35C ) Amyloid precursor protein

(APP)

a-Helix and random coil b-pleated sheet, amyloid (fragment of

APP)

Extracellular

Tauopathies and Alzheimer disease Tau (microtubule binding

protein)

3 and 4 repeat isoforms Hyperphosphorylated aggregated protein Intracellular

Parkinson disease (see Fig. 28-37C ) a-Synuclein Random coil, repeats Aggregated, Lewy bodies Cytoplasmic

Multiple system atrophy a-Synuclein Random coil, repeats Aggregated, Glial cytoplasmic inclusions Cytoplasmic

Huntington disease Huntingtin Trinucleotide repeats Insoluble aggregates Nuclear

Spinocerebellar ataxias Ataxins Trinucleotide repeats Insoluble aggregates Nuclear

Modified from Welch WJ, Gambetti P: Chaperoning brain diseases. Nature 392:23–24, 1998.

Date: 2016-04-22; view: 974