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C A Pardo

Publications and source records attributed to C A Pardo.

30 records · Page 2Linked to original sources
PubMed1995

An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.

Mutations in Cu/Zn superoxide dismutase (SOD1) cause a subset of cases of familial amyotrophic lateral sclerosis. Four lines of mice accumulating one of these mutant proteins (G37R) develop severe, progressive motor neuron disease. At lower levels of mutant accumulation, pathology is restricted to lower motor neurons, whereas higher levels cause more severe abnormalities and affect a variety of other neuronal populations. The most obvious cellular abnormality is the presence in axons and dendrites of membrane-bounded vacuoles, which appear to be derived from degenerating mitochondria. Since multiple lines of mice expressing wild-type human SOD1 at similar and higher levels do not show disease, the disease in mice expressing the G37R mutant SOD1 must arise from the acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Localization of superoxide dismutases in Alzheimer's disease and Down's syndrome neocortex and hippocampus.

Abnormalities in the cellular regulation and expression of antioxidant enzymes may have a role in mechanisms of central nervous system aging and neurodegeneration. We therefore examined, using isozyme-specific antibodies and immunohistochemistry, the localization of copper, zinc-superoxide dismutase and manganese-superoxide dismutase in the frontal and temporal neocortices and hippocampi of aged controls and individuals with Alzheimer's disease or Down's syndrome. Two different antibodies to copper, zinc-superoxide dismutase and one antibody to manganese-superoxide dismutase were evaluated by immunoblotting of homogenates of human brain before use in immunohistochemistry. The copper, zinc-superoxide dismutase antibodies recognized a single band of proteins at 16 kd. The manganese-superoxide dismutase antibody detected a single band of proteins at 25 kd. Immunohistochemically, copper, zinc-superoxide dismutase and manganese-superoxide dismutase immunoreactivities were localized predominantly to neocortical and hippocampal pyramidal neurons and scarcely seen in glial cells in controls. In Alzheimer's disease and Down's syndrome, the distributions and intensities of these two forms of superoxide dismutase immunoreactivities were different as compared with controls. Copper, zinc-superoxide dismutase was enriched in pyramidal neurons undergoing degeneration, whereas manganese-superoxide dismutase was more enriched in reactive astrocytes than in neurons. In senile plaques, copper, zinc-superoxide dismutase-positive globular structures were surrounded by astrocytes highly enriched in manganese-superoxide dismutase. By double label immunohistochemistry, some pyramidal neurons coexpressed superoxide dismutases and tau, and a few copper, zinc-superoxide dismutase-positive structures in senile plaques colocalized with tau. Amyloid cores, diffuse plaques, and microglia scarcely showed colocalization with superoxide dismutase-positive structures. The observed changes in the cellular localization of superoxide dismutases in neocortex and hippocampus in cases of Alzheimer's disease and Down's syndrome support a role for oxidative injury in neuronal degeneration and senile plaque formation. The differential localization of copper, zinc-superoxide dismutase and manganese-superoxide dismutase in cerebral sites of degeneration suggests that cellular responses to oxidative stress is antioxidant enzyme specific and cell type specific and that these two forms of superoxide dismutase may have different functions in antioxidant mechanisms.

Adult↗
PubMed1994

Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems.

In prion diseases, the cellular prion protein (PrPc), abundant in neurons, is converted posttranslationally into an amyloid-forming scrapie prion protein (PrPSc), which accumulates in white matter tracts and nerve terminals. The trafficking of PrPc in neurons was investigated in vivo by injecting [35S]methionine into the L4 and L5 dorsal root ganglia and the entorhinal cortices of adult rats and by tracing the movement of radiolabeled PrPc. In both paradigms, labeled 33-35-kDa PrPc was transported, within 4 h, to distal axons and nerve terminals cofractionating with proteins in the fast component. Future studies using these methods may allow us to determine whether PrPc is converted into PrpSc during axonal transport and whether PrPSc is transported in animals with prion diseases.

Animals↗
PubMed1994

Ventral root avulsion: an experimental model of death of adult motor neurons.

The present study proposes a reproducible model of experimental degeneration of adult motor neurons in the rat. Avulsion of ventral roots in the adult lumbar cord transects motor axons at the root exit and leads to retrograde cell death of 80% of motor neurons 2 weeks later; this result follows a series of retrograde changes, including chromatolysis, loss of transmitter phenotype, and accumulation of phosphorylated neurofilaments in perikarya. Glial cells recruited at the site of retrograde injury express both microglia-specific epitopes (as exemplified by OX-42 immunoreactivity) and macrophage-specific markers (e.g., ED-1 immunoreactivity). Macrophage-specific markers become particularly intense 7 days postaxotomy and provide additional evidence of active phagocytosis of injured neurons. Ventral root avulsion is a very useful model for assessing mechanisms of motor neuron death and testing the ability of trophic factors and other agents to preserve the phenotype and promote the survival of adult motor neurons in vivo.

Animals↗
PubMed1994

Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions.

Tissue sections of brains from patients with multiple sclerosis (MS) and from control individuals were immunostained with MHC class II and glial or vascular endothelial cell antibodies and analyzed by confocal microscopy. MHC class II was abundant in and around actively demyelinating MS lesions and was detected on microglia, phagocytic macrophages, and perivascular macrophages. Astrocytes and vascular endothelial cells were MHC class II-negative. Changes in the size and shape of MHC class II-positive cells associated with MS lesions suggest that microglia transform into phagocytic macrophages, and that they are actively involved in demyelination. Many MHC class II-positive perivascular macrophages within MS lesions contained abundant intracellular MHC class II immunoreactivity; these cells may be involved in antigen presentation and in T cell activation.

Adolescent↗
PubMed1994

Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex.

The cerebral cortices of macaques (ranging in age from 10 to 37 years; n = 17) were analyzed by immunocytochemistry and electron microscopy to determine the cellular and subcellular localizations of the amyloid precursor protein and beta-amyloid protein, the cellular participants in the formation of senile plaques and parenchymal deposits of the beta-amyloid protein, and the temporal/spatial development of these lesions. Amyloid precursor protein was enriched within the cytoplasm of pyramidal and nonpyramidal neuronal cell bodies in young and old monkeys. In the neuropil, amyloid precursor protein was most abundant within dendrites and dendritic spines; few axons, axonal terminals, and resting astrocytes and microglia contained the amyloid precursor protein. At synapses, amyloid precursor protein was found predominantly within postsynaptic elements and was enriched at postsynaptic densities of asymmetrical synapses. The earliest morphological change related to senile plaque formation was an age-related abnormality in the cortical neuropil characterized by the formation of dense bodies within presynaptic terminals and dendrites and an augmented localization of the amyloid precursor protein to astrocytes and microglia. In most monkeys > 26 years of age, the neocortical parenchyma exhibited neuritic pathology and plaques characterized by swollen cytoplasmic processes, interspersed somata of neurons, and reactive glia within or at the periphery of senile plaques. Neurites and reactive astrocytes and microglia within these plaques were enriched with the amyloid precursor protein. In diffuse plaques, nonfibrillar beta-amyloid protein immunoreactivity was visualized within cytoplasmic lysosomes of neuronal perikarya and dendrites and the cell bodies and processes of activated astrocytes and microglia. In mature plaques, beta-amyloid protein immunoreactivity was associated with extracellular fibrils within the parenchyma; some cytoplasmic membranes of degenerating dendrites and somata as well as processes of activated glia showed diffuse intracellular beta-amyloid protein immunoreactivity. We conclude that morphological abnormalities at synapses (including changes in both pre- and postsynaptic elements) precede the accumulation of the amyloid precursor protein within neurites and activated astrocytes and microglia as well as the deposition of extracellular fibrillar beta-amyloid protein; neuronal perikarya/dendrites and reactive glia containing the amyloid precursor protein are primary sources of the beta-amyloid protein within senile plaques; and nonfibrillar beta-amyloid protein exists intracellularly within neurons and nonneuronal cells prior to the appearance of extracellular deposits of the beta-amyloid protein and the formation of beta-pleated fibrils.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1994

Accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse. A model for neuronal ceroid lipofuscinosis.

The motor neuron degeneration (mnd) mutant mouse, initially described as an autosomal semidominant model of motor neuron disease, is characterized by progressive loss of motor activities and the accumulation of lipofuscin-like material in the cytoplasm of neurons in many regions of the nervous system. The stored material is composed of granular, multilamellar, fingerprint, and curvilinear profiles and degenerating mitochondria. These inclusions are associated with the accumulation of subunit c of mitochondrial adenosine triphosphate synthase in an age-dependent pattern. These abnormalities first appear in neurons of the thalamus, hippocampus, and cortex and eventually involve virtually all nerve cells, including those in the retina and enteric nervous system. This type of neuropathology and the presence of subunit c in neurons of mnd mutant mice are characteristic features of neuronal ceroid lipofuscinosis (NCL). The murine disease resembles Batten's disease, an autosomal recessive disorder and the most common NCL in humans. The mnd mouse should be of great value for investigations of the genetics of NCL, for studies designed to delineate the mechanism that lead to neuronal degeneration in these disorders, and for testing novel therapeutic approaches.

Animals↗
PubMed1994

Histologic abnormalities associated with gadolinium enhancement on MR in the initial hours of experimental cerebral infarction.

PURPOSE: To determine the histologic changes associated with gadopentetate dimeglumine enhancement on MR images in acute focal cerebral ischemia. METHODS: In each of two baboons, a microcatheter was used to occlude partially the middle cerebral artery and reduce cerebral blood flow for approximately 3.5 hours. The catheter was then removed allowing reperfusion for approximately 3.5 hours. In two other baboons, cerebral blood flow was completely and irreversibly interrupted by injecting liquid adhesive into the middle cerebral artery. T2-weighted and serial enhanced T1-weighted MR images were obtained. Brain specimens were studied histopathologically. RESULTS: In the animals with incomplete and reversible reduction of cerebral blood flow, postcontrast T1-weighted images obtained during the initial 3 hours of ischemia showed focal areas of hypointensity. These areas were enhanced on later images. The areas of signal abnormality were subsequently found to be necrotic and were characterized by neuronal cytolysis and vascular "plugging." In the animals with complete and irreversible interruption of cerebral blood flow, no abnormal signal intensity or enhancement was observed. Histologic abnormalities were milder in these animals. CONCLUSIONS: Contrast enhancement on MR images in the initial hours of cerebral ischemia was associated with histologic evidence of tissue necrosis but was not associated with milder ischemic changes.

Animals↗
PubMed1990

The human pineal gland in aging and Alzheimer's disease: patterns of cytoskeletal antigen immunoreactivity.

Patients with Alzheimer's disease (AD) and some aged controls may have diminished functions of the pineal gland. In this immunocytochemical study, we stained pineal glands from cases of AD and young and aged controls for cytoskeletal elements and amyloid. We found no evidence of neurofibrillary tangles (NFT) or the accumulation of neurofilaments, tau, A68, or beta/A4 amyloid deposition in pinealocytes or associated structures in cases of AD or controls. In both AD and controls, we observed dense immunoreactivity for phosphorylated neurofilaments in marginal plexuses associated with processes of pinealocytes, boutons, and knob-like endings. The accumulation of phosphorylated neurofilaments in the processes of pinealocytes appears to be a normal morphological characteristic of the pineal gland and may not represent a pathological change.

Adolescent↗
PubMedDate not supplied

Irreversible regional cerebral ischemia: serial MR imaging and proton MR spectroscopy in a nonhuman primate model.

PURPOSE: To delineate the changes in proton MR spectroscopy and imaging that occur with acute, irreversible ischemia of the basal ganglia of a baboon. MATERIALS AND METHODS: The M1 segments of the middle cerebral arteries of six adult male baboons were occluded by endovascular means with microcatheters and N-butyl cyanoacrylate adhesive. Cerebral blood flow measurements were taken with positron emission tomography or radioactive microsphere techniques. Serial spatially localized proton MR spectroscopy of the basal ganglia and MR imaging of the brain were performed. The distribution of ischemic and infarcted tissue was demonstrated by histopathologic techniques or triphenyltetrazolium chloride staining. RESULTS: Radioactive microsphere or positron emission tomography measurements demonstrated no significant cerebral blood flow within the basal ganglia after occlusion of the middle cerebral artery. Proton MR spectroscopy of the basal ganglia demonstrated increasing cerebral lactate and decreasing N-acetyl aspartate within 30 minutes of middle cerebral artery occlusion. Changes in the MR imaging signal intensity of the basal ganglia were observed as early as 3.1 hours on T2-weighted, 3.3 hours on T1-weighted, and 6.1 hours on spin density-weighted images. The distribution of these changes correlated well with the histopathologic features of ischemia and infarction that were seen throughout the basal ganglia. CONCLUSION: Changes in MR imaging signal intensity corresponded to ischemia and infarction in our baboon model of acute irreversible ischemia of the basal ganglia. Increasing cerebral lactate and decreasing N-acetyl aspartate preceded changes in MR imaging signal intensity.

Animals↗