CHAPTER ONE
APPLIED NEUROCYTOLOGY AND BASIC REACTIONS

ASTROCYTES

Astrocytes around capillary-GFAP	Astrocyte-GFAP

Astrocytes (star cells) have radially arranged processes. Their cytoplasm contains intermediate filaments composed of a distinct protein, glial fibrillary acidic protein (GFAP). Antibodies against this protein are routinely used to demonstrate reactive and neoplastic astrocytes. Historically, GFAP was the first immunostain to be used. Astrocytes are important for structural support of the CNS. Their processes form the glia limitans, a membrane that seals the external surface of the CNS. During brain development, astrocytic processes (radial glia) guide neurons in their migration from the wall of the ventricles to the cortex.

Astrocytic foot processes surround brain capillaries and, during development, induce endothelial cells to form tight junctions. The endothelial tight junctions are the basis of the blood-brain barrier, a system of controlled transcapillary transport which maintains homeostasis in the CNS. Endothelial tight junctions are found only in brain capillaries. Loss of the integrity of the endothelial barrier causes fluid to leak into the interstitial space, leading to vasogenic cerebral edema. This raises intracranial pressure and can collapse brain capillaries, resulting in arrest of cerebral perfusion. Cerebral edema is caused by a variety of pathological processes, including ischemic insults, inflammation, and malignant brain tumors whose capillaries do not have tight junctions. Astrocytes are less vulnerable than neurons to ischemic injury but they are damaged if there is lactic acidosis. Such damage causes intracellular fluid accumulation (cytotoxic edema). Cytotoxic edema involves the cerebral cortex, whereas vasogenic edema is more pronounced in the white matter. Vasogenic edema is more important clinically than cytotoxic edema.

Astrocytes are important for neurotransmitter synthesis and regulation of the metabolic activities of neurons. They take up and recycle GABA and glutamate that are released at synaptic clefts. Glutamate is converted to glutamine by glutamine synthetase. Glutamine is then released into the extracellular space, taken up by neurons, and converted to glutamate by glutaminase. Astrocytes also produce new glutamate from glucose via the tricarboxylic acid cycle. This replenishes glutamate lost through oxidative degradation. Without astrocytes, neurons would not have their most important neurotransmitter. In addition, astrocytes influence synaptic activity by releasing glutamate directly into the extracellular space. Astrocytes are also important for maintaining proper ionic balance in the extracellular fluid.

Gemistocytic astrocytes	Reactive astrocytes-GFAP	Alzheimer II astrocytes

When neurons are lost and brain tissue is damaged from whatever cause, astrocytes proliferate, fill the gaps, and restore CSF-brain and blood-brain barriers. This process, which is called gliosis, is for the CNS what scarring is for extraneural tissues. Astrocytes participating in gliosis are referred to as reactive astrocytes. They have a large cytoplasmic mass, long, branching processes, and increased cytoplasmic filaments. Such astrocytes are also known as gemistocytic astrocytes from a Greek word that means to fill up. In acute metabolic disorders such as hepatic encephalopathy, hyperammonemia, and cerebral ischemia, astrocytes enlarge. Their nuclei are large and appear clear in H&E stains. In hyperammonemia, they also accumulate glycogen. Such cells are called Alzheimer type II astrocytes. This probably reflects a poorly understood role of astrocytes in metabolic dysfunction.

Rosental fibers	Corpora amylacea

Rosenthal fibers are homogeneous, eosinophilic, elongated, or globular inclusions in astrocytic processes. They have a filamentous and granular structure and contain GFAP. They are seen in old brain scars dating back to childhood, and in some low-grade astrocytomas. Mutations of GFAP cause Alexander disease, characterized by diffuse deposition of Rosenthal fibers, resulting in white matter degeneration and neurological dysfunction. Corpora amylacea are spherical intracytoplasmic bodies of carbohydrate polymers that develop in astrocytic processes with advancing age. They have no pathological significance. The astrocyte is the cell in the adult mammalian brain most capable of undergoing mitosis. Most brain tumors are derived from astrocytes (astrocytomas).