Hirano Bodies Research Articles

Hirano bodies and other cytoskeletal abnormalities develop in fetal rat CNS grafts isolated for long periods in peripheral nerve

Dissociated cells from the telencephalic region of 12-day-old rat embryos were cultured in vitro for 3–5 days and transplanted into segments of the sciatic nerve of adult inbred rats. Transplanted progenitor cells survived, differentiated, and expressed various morphological and molecular features characteristics of neurons and glia. Six to twelve months after grafting, many neurons underwent changes compatible with an alteration of their cytoskeleton. These included; (1) a strong perikaryal immunoreactivity to the monoclonal antibody RT97, directed against the 200-kDa phosphorylated neurofilament subunit and (2) the formation of Hirano bodies within dendrites. Similar cytoskeletal abnormalities are seen as part of the spectrum of changes that occur in some human neurodegenerative diseases and in aging. The approach we have used may provide new possibilities for the study of the pathogenesis of these lesions under controlled laboratory conditions.

The digital structural analysis of helical hirano bodies obtained by electron microscopy

A digital structural analysis method with the aid of a scanning densitometer was successfully applied to paracrystalline inclusion bodies which have been found in the brains of humans exhibiting senile dementia. Based on Fourier techniques involving noise removal and enhancement for structural analysis from a computer-generated diffractogram, it is proposed that the crystalline bodies from thin sections of the specimen constitute a stranded helix of 18.5 nm pitch. From the digital processed data obtained from the various different electron micrographs obtained by the use of a tilting device, a three-dimensional model and Fourier synthetic images representing the precise arrangement of the Hirano body stranded helix are derived and graphically demonstrated.

Sequestration of Tubulin in Neurons in Alzheimer's disease

In Alzheimer's disease (AD), a variety of populations of neurons exhibits cytoskeletal abnormalities, including neurofibrillary tangles (NFT) in perikarya, Hirano bodies in dendrites and filament-distended axons/terminals/dendrites (neurites) in senile plaques. Some nerve cells, particularly pyramidal neurons of the hippocampus, also develop Hirano bodies (paracrystalline arrays of actin) and granulovacuolar degeneration (GVD; granular inclusions in cytoplasmic vacuoles). Since abnormalities of cytoskeletal elements have been implicated in the formation of NFT, neurites and Hirano bodies, the present study was designed to determine whether GVD also may represent a type of cytoskeletal pathology. Sections of hippocampus from controls and from individuals with AD were stained by immunocytochemical methods using monoclonal and polyclonal antibodies directed against a variety of cytoskeletal antigens. Granules of GVD contained tubulin-like immunoreactivity and absorption with purified tubulin abolished staining. Other antigens were not demonstrated in granules when antibodies directed against other cytoskeletal antigens were used. The observation of sequestration of tubulin in granules is consistent with the concept that abnormalities of the neuronal cytoskeleton are an important part of the cellular pathology of AD.

Abnormalities of dendritic actin organization in the brindled mouse

The brindled mouse is an X-linked mutant with alterations in copper homeostasis. Ultrastructural analysis of the cerebellum and neocortex reveals several dendritic abnormalities, including the formation of Hirano bodies and other cytoskeletal alterations. Immunocytochemical evidence demonstrates that actin is a component of these microfilament lattices.

Microscopic Globular Bodies in the Human Brain

Microscopic globular bodies (MGB) in the neuropil of gray matter are different from other previously reported structures such as corpora amylacea, axonal spheroids and Hirano bodies. They are brilliantly eosinophilic with the hematoxylin and eosin (H&E) stain, measure 1-10 microns in diameter, and are seen in the neuropil of the gray matter, chiefly in the cerebral cortex. Ultrastructurally, MGB are osmiophilic and globular, and located within a cytoplasmic process. They are homogeneous, finely granular, and surrounded by a ruffled membrane. The processes in which MGB are found, contain a few organelles or may be empty. Synaptic junctions are often present on the cytoplasmic process containing MGB. Quantitative studies of MGB reveal a striking correlation with age. Compared with controls, MGB are fewer in number in neurological disorders with mental retardation or dementia. Microscopic globular bodies (MGB) are similar to the dense microspheres described by Averback and have been previously reported by the author as eosinophilic globular bodies. The present study discloses some features of MGB to be similar to the bodies described by Averback, although there are some discrepancies in the reported staining reactions and in the interpretation that these bodies have some relationship to senile plaques. In the few animals studied (five rats, one pig and one monkey) MGB were found only in the pig.

Dementia of Alzheimer type (DAT)--a review of its morbid anatomy.

The most important morphological findings in dementia of Alzheimer type (DAT) are Alzheimer neurofibrillary tangles, senile plaques, amyloid angiopathy, granulovacuolar degeneration and Hirano bodies. The morphological and immunocytochemical findings in these changes are described, in particular those related to the pathological cytoskeleton. Their possible relationship to the disturbed synthesis of neurotransmitters recently demonstrated is considered, and their relevance for the clinical syndrome of dementia is discussed. Hypothetical etiologies (ageing per se, genetics, infection and chronic intoxication) are briefly mentioned.

The structure analysis of Hirano bodies by digital processing on electron micrographs.

To clarify the structure of Hirano bodies, electron micrographs of Hirano bodies taken at various tilting angles have been studied by digital image analysis. On the electron micrographs, the beaded filaments of Hirano bodies were turned into a pattern of lattice-like arrays by changing the tilting angles. Based on computer-processed diffraction patterns and filtered images, it is proposed that the filaments of Hirano bodies are helical strands with a pitch of 185 A. A model for the helical strand drawn by microcomputer at various angles of rotation is in accordance with the filtered images of the tilted filaments. Computer simulation also reveals that the helical strands appear to be lattice-like when they are arranged in parallel.

Filamentous arrays reminiscent of tropomyosin crystals in Hirano bodies of Alzheimer's disease

Distinctive acidophilic rods, Hirano bodies, have been observed in brains of patients under a variety of pathological conditions, including Alzheimer's disease, and also in normal, aged individuals. Data on the three-dimensional conformation and on the chemical composition of these structures are presently controversial. The presence of actin in Hirano bodies has been indicated immunocy tochemically. Other authors have proposed that Hirano bodies are crystalline arrays of ribosomes attached to membranes. We report here the results of an investigation of Hirano bodies in the brains of Alzheimer's patients. Applying the techniques of three-dimensional electron microscopy, we have demonstrated as a major component of the Hirano bodies, characteristic arrays of filamentous proteins reminiscent of tropomyosin crystals produced in vitro.Frontal lobe biopsies from 3 patients with pre-senile dementia diagnosed as Alzheimer's disease were investigated by three-dimensional electron microscopy. Fig. 1 is a survey of a Hirano body occupying the main portion of a neurite. It is comprised of sheets of filaments forming characteristic network patterns.

The association of actin with Hirano bodies.

Ultrastructural studies of the rod-shaped eosinophilic inclusions of the hippocampus (Hirano bodies) have demonstrated thin, filamentous components. The size of the filaments suggests that actin polymers (microfilaments) might form part of the Hirano body. To investigate this possibility, sections of human hippocampus and neocortex were stained, using a peroxidase-antiperoxidase (PAP) technique, with an antiserum against actin. Dense reaction product was seen over rod-shaped bodies, the location and morphology of which were typical of Hirano bodies. Immunocytochemical reactions on tissue previously stained with hematoxylin and eosin allowed a direct comparison between Hirano bodies, identified by their shape and eosinophilia, and the PAP reaction product. These results suggest an abnormal organization of a major cytoskeletal protein in hippocampal neurons, especially those of aged brains.

Hirano body in extraocular muscle.

Thirty-three rectus superior extraocular muscles from 23 autopsy cases, all over 60 years, were examined. Eosinophilic inclusions (Hirano bodies) were observed in all the muscles; they were stained deep red by Masson's trichrome stain and were positive for protein stain. They consisted of a collection of filamentous structures of two types: (1) a regular array of filaments 100 A in diameter which sometimes were arrayed in perpendicular planes and (2) another type in a herring bone or ladder-like pattern. Both structures were closely associated with the accumulated thin filaments 50-60 A in diameter (actin?) in the subsarcolemma. The frequent appearance in aged muscle fibers of Hirano bodies indicates that their formation is a change closely related with aging.

Neurofibrillary changes in human brain. An immunocytochemical study with a neurofilament antiserum.

Brain samples from cases of Alzheimer's disease, postencephalitic Parkinson's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Pick's disease, as well as from a case of Alzheimer's disease with a large number of Hirano bodies, were stained with the peroxidase-anti-peroxidase method using an antiserum previously shown to immunoreact with normal neurofilaments and neurofilament polypeptides. The specificity of this serum was confirmed by absorption an purified neurofilament proteins. Neurofibrillary tangles of Alzheimer's disease, postencephalitic Parkinson's disease, and progressive supranuclear palsy, Pick's bodies, and the fibrillary inclusions of amyotrophic lateral sclerosis were all immunostained. Hirano bodies showed no immunostaining. Thus, with the exception of the Hirano bodies, all the neuronal fibrillary inclusions examined appeared to share common antigenic characteristics. The orgin of all these structures from normal neurofilaments is postulated.

“Limbic Predilection in Alzheimer Dementia: Is Reactivated Herpesvirus Involved?”

In the brains of patients with senile dementia of the Alzheimer type (SDAT), the quantitatively pathognomonic neuronal lesions (tangles, plaques, granulovacuolar degeneration, Hirano bodies, and nerve cell loss) are predisposed to occur especially within the limbic system. Anatomical and physiological studies indicate that fibres from the trigeminal ganglia innervate meninges and vessels within the middle and anterior cranial fossae, especially in the same subfrontal and mesial temporal regions preferentially afflicted in acute herpes encephalitis. These limbic regions are critical for normal memory processing and recall. Explantation and cocultivation techniques have recently demonstrated Herpes simplex virus in many humans trigeminal ganglia, which also reveal a life-long lymphocytic infiltration in the absence of any pathological changes in the sensory neurones. These lymphocytes may represent a histological marker of latent herpes virus, which when reactivating is well-established as the ganglionic source of recurrent herpes labialis. It is suggested that reactivation of the same dormant viral material travelling centripetally instead might be the cause of the "degenerative" lesions typical both of Alzheimer's Disease and of the normal aged human brain.

Hirano bodies in myelinated fibers of hepatic encephalopathy.

Inclusions, essentially identical to Hirano bodies, were observed in the substantia nigra, dentate nuclei, and frontal lobes in three autopsy cases of hepatic encephalopathy. Similar inclusions were not observed in these areas in nine controls. The inclusions were mainly seen in the inner loops of the myelinated fibers, between the myelin lamellae, and among degenerated myelin sheaths. The same inclusions were rarely observed in postsynaptic terminals.

Etude anatomo-pathologique et ultrastructurale de divers processus de vieillissement cérébral chez l'homme revue critique

Although the primary interest in the course of studies on aging is focused on problems of function, morphology has an important role to play as a marker and as a control. Processes concomitant with brain aging are multiple and diverse. They ought to be correlated individually with functional changes. Statistical problems in population sampling for reference morphological studies are difficult. Bias is often a consequence of unstated underlying theories (Brain aging: a physiological process v. one of many pathological processes). Morphological criteria do not allow close application of animal models to aging problems in the human. The review considers the following lesions: 1. Brain shrinkage; 2. Neuronal loss; 3. Alterations in the outline of neurons; 4. Lipofuscin accumulation; 5. Corpora amylacea; 6. Senile plaques and amyloid deposits; 7. "Neurofibrillar degeneration"; 8. "Granulovacuolar degeneration"; 9. Hirano bodies. Vascular changes and their consequences are not considered. Lesions in the first group (1 to 5) are interpreted as non-specific and non-specifically correlated with aging; their correlation with functional loss is low. Lesion in the second group (6 to 9), on the contrary, are strongly correlated with each other and with dementia; they are interpreted as characteristic, not of aging itself, but of a widespread pathological condition: Alzheimer's disease sensu lato. A current line of research involves the hypothesis of a viral origin of this condition.

Crystalline ribosomes are present in brains from senile humans.

Paracrystalline inclusions known as Hirano bodies characteristically appear in the hippocampal region of the brains of humans exhibiting senile and presenile dementias as well as several other neurodegenerative diseases. We present evidence that the currently accepted model for those structures based on alternating filament sheets is not correct, but that Hirano bodies are stacked sheets of membrane-bound ribosomal particles derived from partially degraded rough endoplasmic reticulum or Nissl substance. Using fluorescence staining with acridine orange and ethidium bromide, were have shown that the bodies contain RNA. Spatial filtering of electron micrographs by Fourier techniques shows that the individual particles that make up the arrays have a characteristic shape previously reported for the large subunit of eukaryotic ribosomes. The storage of these ribosomal particles in inclusion bodies may indicate a quiescent state of protein synthesis in the cells. This withdrawal of synthetic mechanisms in the hippocampus may have significant consequences in the loss of ability to consolidate short-term to long-term memory.

Changes with age in the peripheral nerves of the rat. An ultrastructural study.

Ultrastructural observations have been made on the tibial and plantar nerves of Wistar rats aged 18-24 months. Changes indicative of segmental demyelination and remyelination and axonal degeneration and regeneration were prominent in the plantar nerves. Both in the plantar and tibial nerves, but particularly in the former, axonal abnormalities were frequent. These included the occurrence of multiple intra-axonal vacuoles containing glycogen and polyglucosan bodies. Axonal sequestration by adaxonal Schwann cell processes was also increased. The Schwann cell cytoplasm in relation to this activity contained bundles of filaments with the ultrastructural features of Hirano bodies. The changes in the plantar nerves probably indicate a pressure neuropathy, but the possibility of a superimposed distal axonal degeneration related to aging cannot be excluded on the present evidence. Such changes must be taken into consideration in experimental studies performed on rats of this age.

Topography of Pick Inclusion Bodies in Hippocampi of Demented Patients

Topographic analysis was performed on the distribution of argyrophilic inclusions in hippocampal neurones of patients with Pick's dementia. A semiautomated scanning stage microscope linked potentiometrically to an XY pen recorder permitted the plotting of cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of Pick body-bearing nerve cells per cubic mm. of (pyramidal) cortex was quantified by measuring the area of each of six "zones" with a digitizer and programmable calculator. The ranking orders of relative severity showed that neurones in Rose's H1 field, the adjacent subiculum, and the entorhinal cortex are severely involved; that H2 and the presubiculum are less afflicted; and that the endplate is the least affected of all. The similarity of these predilections to those already demonstrated for Hirano bodies, granulovacuoles and neurofibrillary tangles in Alzheimer's disease suggests that a specific neurotransmitter defect may also underlie the dementia of Pick's disease.

Crystalloid inclusions reminiscent of Hirano bodies in autolyzed peripheral nerve of normal Wistar rats

In a study of experimental autolysis of peripheral nerves of normal Wistar rats, crystalloid inclusions similar to Hirano bodies were observed. They occurred in the nuclei and cytoplasms of Schwann cells and in myelinated axons. They first developed after a 12-h autolysis and increased in number and size with time. Their fine structure, localization, and morphogenesis are discussed in relation to the autolysis of the cellular organelles.

Morphogenesis of the Hirano body in neurons of the squirrel monkey dorsal horn

Electron microscopic investigation of laminae I-III in the lumbosacral region of the squirrel monkey spinal cord has disclosed possible stages in the morphogenesis of the Hirano body. These bodies occur occasionally in nerve cell bodies and dendrites. They are round to oval in shape, measure up to 2.2 micrometer in diameter and are composed of circular layers of 10 nm filaments. In several instances in the present study, Hirano bodies were observed in close association with the Golgi apparatus. Here Golgi-related vesicles were attached to the external surface of the Hirano bodies. In one instance a cluster of developing Hirano bodies of various sizes was observed. The smaller bodies were located nearest the Golgi apparatus while the larger were further away. In this case several short filaments, which may be precursors of the longer filaments which make up the layers of the inclusion, were observed in the cytoplasm between the Golgi cisternae and the smaller Hirano bodies. These observations suggest that the Golgi apparatus plays a major role in the production of the Hirano body. The significance of the occurrence of these inclusions is discussed.

Light and electron microscopic observations on the relationship between Hirano bodies, neuron and glial perikarya in the human hippocampus

Hippocampi from two intellectually normal and four demented subjects were examined in autopsy material. Large Hirano bodies seen by light and electron microscopy were thought to be glial in origin and not to be produced by the perikarya of neurons as has been suggested in the literature. Myelination of two Hirano bodies found in the stratum lacunosum-granulosum where neuron perikarya are rare suggests that these bodies are produced by oligodendroglia. Hirano bodies were found to be associated with neurons showing granulovaculoar degeneration. With electron microscope they were frequently seen to be divided by clefts filled with amorphous material which possibly consisted of free ribosomes.