notes by dr Claudio Italiano
Neuronal damage can be an acute process, e.g. determined by a stroke, which always derives from the suffering of the nerve cell, consequence of depletion of oxygen or glucose due to vascular events, in the sense that the cerebral circulation is interrupted either by an ischemic or hemorrhagic block of the same; in other cases it is a brain trauma, or a slower process, often associated with accumulation of abnormal protein aggregates, as occurs in degenerative brain disorders.
Neurons require a continuous supply of oxygen and glucose to meet the metabolic
needs.
This fulfills the physiological and anatomical needs of the cells, including the
maintenance of membrane gradients, which are essential for action potentials,
and the support of the cytoplasmic extension of the dendritic arborization of
neurons and axons, which can extend to a large distance from the cell body (over
1 m in adults).
Since most mature neurons are maintained throughout an individual's life span,
protein turnover and quality must be precisely regulated to ensure cellular
integration. It is not surprising that many neurological diseases derive from
the harmful effects due to the accumulation of proteins with a conformational
defect (proteinopathy).
Acute neuronal damage ("red neuron"): refers to a spectrum of alterations,
related to hypoxia / acute CNS ischemia or other acute insults, which constitute
the first morphological indicators of neuronal cell death.
The "red neurons" are observed after about 12-24 hours from the irreversible
hypoxic / ischemic insult. The morphological characteristics are constituted by
a contraction of the cell body, nucleus pycnosis, disappearance of the nucleolus
and loss of the substance of Nissl, with intense eosinophilia of the cytoplasm.
Subacute and chronic neuronal damage ("degeneration"): s refers to neuronal
death that manifests itself in long-lasting progressive neurodegenerative
diseases, characterized by slow evolution, such as amyotrophic lateral sclerosis
and Alzheimer's disease.
The typical histological characteristic consists of cellular loss, which often
selectively affects groups of functionally related neurons, and in a reactive
gliosis.
In the early stages, cell loss is observed with difficulty and often the best
indicators of neuronal damage are represented by associated glial alterations.
For many of these diseases, there is evidence that cell loss occurs due to
apoptotic death.
Axonal reaction: it is an alteration that is observed in the cell body during
the axon regeneration; it is more evident in the neurons of the anterior horns
of the spinal cord when the motor axons are severed or seriously damaged.
There is an increase in the protein synthesis associated with axonal budding.
The morphological variations observed in the pericaral include the enlargement
and rounding of the cell body, the peripheral localization of the nucleus, the
enlargement of the nucleolus and the dispersion of the Nissl substance from the
center towards the cell periphery (central chromatolysis).
Neuronal damage can be associated with a wide spectrum of subcellular changes in
neuronal organelles and in the cytoskeleton. Neuronal inclusions may represent a
manifestation of aging, when there are intracytoplasmic accumulations of complex
lipids (lipofuscin), proteins or carbohydrates.
An abnormal cytoplasmic deposition of complex lipids and other substances also
occurs in genetically determined metabolism disorders, in which substrates or
their intermediate products accumulate. Viral infections can lead to abnormal
intranuclear inclusions, as seen in herpetic infections (Cowdry bodies), to
cytoplasmic inclusions, as observed in rabies (Negri bodies) or both, as in
cytomegalovirus infections.
Some degenerative CNS diseases are associated with neuronal intracytopiasmatic
inclusions, such as neurofibrillary clusters of Alzheimer's disease and Lewy
bodies of Parkinson's disease; others cause abnormal vacuolization of the
pericar and neuronal cellular processes (Creutzfeldt-Jakob disease).
Gliosis, regardless of etiology, is the most important histopathological
indicator of CNS damage and is characterized by both hypertrophy and astrocyte
hyperplasia. The astrocyte takes its name from its star-like appearance.
These cells possess branched and multipolar cytoplasmic processes, which
protrude from the cell body and contain glial fibrillary acidic protein (GFAP),
a cellular-specific intermediate filament.
Astrocytes act within the brain as metabolic buffers and as detoxifiers. In
addition, through pedunculated processes, which surround the capillaries or
extend to the subpocal and subependymal regions, they contribute to the barrier
functions and control the flow of macromolecules between the blood,
cerebrospinal fluid LCR) and the brain.
In gliosis, the nuclei of the astrocytes, which are typically round or oval (10
micron wide), with a uniformly distributed pale chromatin, enlarge, become
vesicles and develop prominent nucleoli. The previously poor cytoplasm expands
to take on the appearance of a bright, somewhat irregular pink band around an
eccentric nucleus, from which numerous squat and branched processes emerge (gemistocytic
astrocytes).
Acute cellular damage, as seen in hypoxia, hypoglycaemia and toxic damage,
manifests itself in cell edema, as in other cells. A type II astrocyte of
Alzheimer's (which is not related to Alzheimer's disease, but was first
described by the same physician) is a cell of the gray substance with a large
nucleus 2-3 times normal, a central chromatin pale, an intranuclear glycogen
droplet and a prominent nuclear membrane and nucleolus.
This type of anomaly is observed especially in individuals with long-term
hyperammonaemia due to chronic liver disease, Wilson's disease or hereditary
metabolic disorders of the urea cycle.
Other types of cell damage lead to the formation of cytoplasmic inclusions.
Rosenthal fibers are rather irregular, thick, elongated and intensely
eosinophilic structures that are located in astrocytic processes; they contain
two heat-shock proteins (alphaB-crystalline and hsp27) and ubiquitin. Rosenthal
fibers are typically present in the areas of long-standing gliosis; they are
also characteristic of a glial tumor, the pilocytic astrocytoma.
In Alexander's disease, a leukodystrophy associated with mutations in the gene
that codes for GFAP, Rosenthal fibers are found in large quantities in the
periventricular, perivascular and subpial sites.
More often observable are the starchy bodies, or polyglucosan bodies. These are
concentric, spherical, weakly basophilous, PAS-positive, lamellar structures,
with a diameter between 5 and 50 microns, located wherever astrocytic terminal
processes exist, especially in the sub-areas and perivascular areas. They
consist mainly of glycosaminoglycan polymers, H5P proteins and ubiquitin.
It is believed that they represent a degenerative alteration of astrocytes and
increase in number as we age. Lafora bodies, which are observed in the cytoplasm
of neurons (as well as hepatocytes, myocytes and other cells) in individuals
with myoclonic epilepsy (myoclonic epilepsy at Lafora bodies), are characterized
by a similar biochemical and structural composition.
Microglia is made up of phagocytic cells derived from the mesoderm which act as
resident macrophages of the CNS. They share many surface markers with peripheral
monocytes / macrophages (for example, CR3 and CD68). Respond to the damage with:
(1) proliferation; (2) development of elongated nuclei (rod cells), as in
neurosyphilis; (3) formation of aggregates around small areas of tissue necrosis
(microglial nodules); or (4) grouping around the cell bodies of necrotic neurons
(neuronophagia).
In addition to resident microglia, blood-derived macrophages may also be present
in inflammatory sites.
Reactions of other glial cells to damage
Oligodendrocytes are cells that encompass their cytoplasmic processes around the
axons to form myelin. Each oligonedendrocyte myelinates several internodes on
multiple axons, as opposed to Schwann cells that mielize peripheral nerves with
a one-to-one correspondence between cells and internodes. The damage or
apoptosis of oligodendroglial cells is a characteristic of acquired
demyelinating disorders and leukodystrophies.
In progressive multifocal leukoencephalopathy, oligodendroglial nuclei may
contain viral inclusions. Glial cytoplasmic inclusions, mainly composed of
a-sinuclein, are found in oligodendrocytes in multiple systemic atrophy (MSA).
Ependymal cells, ciliated cylindrical epithelial cells that line the ventricles,
do not have specific reaction patterns.
When inflammation or marked dilatation of the ventricular system occurs, the
disruption of the ependymal lining is combined with the proliferation of
subependymal astrocytes to produce small irregularities on the ventricular
surfaces (ependymal granulations).
Some infectious agents, especially CMV, can determine extensive ependymal damage
associated with the presence of viral inclusions in ependymal cells. In any
case, neither oligodendrocytes nor ependymal cells provide significant responses
to most forms of CNS damage.