Pathogenesis and pathology of scrapie after stereotactic injection of strain 22L in intact and bisected cerebella.

The mechanisms involved in the spread of scrapie within the brain remain unclear. To examine this issue the 22L scrapie strain was injected in one side of the cerebellum of mice in which the cerebellum had been bisected prior to injection. Another group of animals received the same injection into intact cerebella, i.

Vacuolization, incubation period and survival time analyses in three mouse genotypes injected stereotactically in three brain regions with the 22L scrapie strain.

In previous studies we showed that C57BL mice injected stereotactically in the cerebellum with the 22L scrapie strain had a significantly shorter incubation period than those injected with the same agent in other brain regions. In mice injected in the cerebellum, vacuolization was limited to the cerebellum, medulla and mesencephalon, whereas injection into forebrain regions resulted in vacuolization in all brain regions. The studies suggested that the cerebellum had a selective vulnerability for 22L.

Changes in the distribution of anionic sites in brain micro-blood vessels with and without amyloid deposits in scrapie-infected mice.

Cationic colloidal gold (CCG) and scrapie-infected mouse brain samples embedded in Lowicryl K4M were used for ultrastructural localization of negatively charged microdomains (anionic sites) in the cerebral microvasculature. The distribution of anionic sites on both fronts (luminal and abluminal) of endothelial cells and in the basement membrane (BM) in the majority of micro-blood vessels (MBVs) located outside the plaque area and in the remaining cerebral cortex was similar to that which has been previously observed in non-infected animals. Some MBVs (especially capillaries), however, located inside the plaque areas and surrounded directly by amyloid fibers contained attenuated endothelium, the luminal surface of which showed a segmental lack or diminution of anionic sites.

Alzheimer neuropathology in non-Down's syndrome mentally retarded adults.

We examined the brains of 385 mentally retarded adults aged 23-90 years without Down's syndrome (DS), metabolic disorder, or hydrocephalus to extend our knowledge about the occurrence of Alzheimer-type neuropathology in this population. Relevant measures of neuropathology also were related to selected information available from clinical records. The presence of one or more neurofibrillary tangles (NFT) and/or neuritic plaques (NP) was observed in 63.

Study of spindle microtubule reassembly in cells from Alzheimer and Down syndrome patients following exposure to colcemid.

Numerous intraneuronal neurofibrillary tangles and senile (neuritic) plaques are the two characteristic lesions in Alzheimer disease (AD) and adult Down syndrome (DS). Evidence indicates that microtubule assembly is impaired in AD. We studied spindle microtubule repolymerization rates in EBV-transformed lymphoblasts from AD, DS, and control individuals after colcemid exposure.

Incubation periods and histopathological changes in mice injected stereotaxically in different brain areas with the 87V scrapie strain.

After stereotaxic injection into five different brain areas (cortex, caudate nucleus, substantia nigra, thalamus and cerebellum) of IM mice with the 87V scrapie strain, the cerebellum had the shortest incubation period. The vacuolation pattern was similar regardless of the area injected with extensive vacuolation in the thalamus, mesencephalon and hypothalamus. The pattern of amyloid plaques differed markedly depending on the area injected.

The complex of microglial cells and amyloid star in three-dimensional reconstruction.

Ultrastructural, three-dimensional reconstruction and morphometric studies of classical plaques from the cortex of a patient with Alzheimer's disease showed five or six microglial cells, which form, together with the amyloid star, the central complex of the classical plaque. Microglial cells associated with the amyloid star show marked polymorphism, but all forms possess an amyloid making pole. The surface of the cell membrane at this pole is extended by apparent connection with membranes of cytoplasmic channels filled with amyloid fibers.

The mRNA encoding the scrapie agent protein is present in a variety of non-neuronal cells.

PrP 27-30, a unique protease-resistant protein associated with scrapie infectivity, derives from the proteolytic cleavage of a larger precursor encoded by a host gene. To identify sites of PrP biosynthesis, in situ hybridization was done using cloned PrP cDNA as a probe. In rodent brain, PrP mRNA was expressed in neurons, ependymal cells, choroid plexus epithelium, astrocytes, pericytes, endothelial cells and meninges of both scrapie-infected and uninfected animals.

Ultrastructure of the cells forming amyloid fibers in Alzheimer disease and scrapie.

Ultrastructural, three-dimensional reconstruction of cells surrounding the amyloid star in classical plaques in Alzheimer disease (AD) and histochemical studies of the cells associated with the deposits of amyloid fibers in scrapie were carried out. These studies showed that in both diseases, the fibers appear within the smooth endoplasmic reticulum (ER) and infoldings of cytoplasmic membranes of microglia/macrophages. Additional information about the site of formation of the amyloid fibers derives from histochemical studies of the localization of nucleoside diphosphatase (NDPase) activity.

Ultrastructural studies of the cells forming amyloid fibers in classical plaques.

Three-dimensional reconstruction and ultrastructural studies of classical plaques from the cortex of patients with Alzheimer's disease showed that microglial cells of the plaques are the amyloid-forming cells. The amyloid star of the single plaque represents the product of five or six microglial cells covering about 80% of the amyloid star surface. The amyloid fibers appear to be formed within altered cisterns of the endoplasmic reticulum.

Cytoskeletal protein pathology and the formation of beta-amyloid fibers in Alzheimer's disease.

Discovery of the abnormally phosphorylated tau in paired helical filaments, its accumulation preceding the formation of the tangles and the in vitro microtubule assembly defect suggest that an abnormality in the protein phosphorylation/dephosphorylation system is involved in the pathogenesis of Alzheimer cytoskeletal pathology. The levels of mRNA for the beta-amyloid precursor protein (beta APP) in the brain suggest that only a small deficiency in the processing of the precursor would be sufficient to account for the accumulation of beta-amyloid in Alzheimer brain. Identification of reticuloendothelial system cells responsible for the production/processing of beta-amyloid will help to elucidate the pathogenesis of the brain amyloidosis.

Postmortem detection of measles virus in non-neural tissues in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis, a rare, progressive, fatal central nervous system disease of children, is caused by measles virus. Clinical signs occur months to several years after recovery from acute measles infection. It is not known where the virus persists while the disease is inapparent.

Nerve regeneration patterns after acute ischemic injury.

We performed morphologic studies on regeneration of the cat's hind limb nerves, following simultaneous ligation of the aorta and right femoral artery. There were 2 regeneration patterns depending on the extent of ischemic necrosis. When nerve infarcts were limited only to intrafascicular regions, there was no basic change of nerve microarchitecture during regeneration.

Amyloid protein and neurofibrillary tangles coexist in the same neuron in Alzheimer disease.

In Alzheimer disease, paired helical filaments accumulate in the neuron, and amyloid fibers are found in the extracellular space in the neuropil and brain vessels. Amyloid and paired helical filaments are morphologically distinct. Although messenger RNA that encodes the amyloid has also been shown in several tissues, including brain, the intracellular expression of the protein has not been observed.

A spirohydantoin derivative of oxymorphone: an agonist with delayed antagonist activity.

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting.

Alzheimer-type neuropathology and clinical symptoms of dementia in mentally retarded people without Down syndrome.

Postmortem morphometric analyses of Bielschowsky stained sections from brains of 70 mentally retarded people without Down syndrome, age 65 and over when they died, indicated Alzheimer-type neuropathology in 22 cases (31%) and a majority with at least presence of some Alzheimer-type lesions. Based upon information abstracted from clinical histories, however, old-age-associated dementia proved to be difficult to judge reliably. Nevertheless, for otherwise healthy individuals (n = 25), loss of motor skills, development of problem behaviors, and a 10-point drop in IQ appeared to be likely indicators of Alzheimer's disease.

Immunoreactivity of neuronal lipofuscin with monoclonal antibodies to the amyloid beta-protein.

Monoclonal antibodies generated against a synthetic peptide corresponding to amino acids 1 to 24 of cerebrovascular amyloid beta-protein do not only stain amyloidotic blood vessels and the amyloid deposits of the (senile) neuritic plaques, but also the neuronal pigment lipofuscin. Staining of lipofuscin is observed in both cerebral and cerebellar cortices, subcortical nuclei as well as the brain stem, and is identical in Alzheimer and normal control brain. Western blots of a lipofuscin enriched fraction show an anti-beta-protein reactive polypeptide migrating at approximately 31 kDa position on SDS-polyacrylamide gel electrophoresis.

Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease.

The intraneuronal accumulation of paired helical filaments in the form of neurofibrillary tangles is one hallmark of the brain pathology in Alzheimer's disease. At certain predilection sites, a small number of similar lesions are also present in the brains of the majority of aged non-demented individuals. As suggested by several studies before, these abnormal cytoskeletal structures contain determinants of microtubule-associated protein tau and ubiquitin.

Sites of egress of inflammatory cells and horseradish peroxidase transport across the blood-brain barrier in a murine model of chronic relapsing experimental allergic encephalomyelitis.

Results are reported of experiments designed to focus at attachment sites of inflammatory cells (ICs) on the luminal surface of brain endothelial cells (ECs) and on the mechanisms of horseradish peroxidase (HRP) transport across the altered blood-brain barrier (BBB) in a murine model of chronic relapsing experimental allergic encephalomyelitis. Cationized ferritin (CF) served as a marker for evaluating the electrostatic nature of brain microblood vessels (MBVs) on the plasma membranes of ICs or normal mouse peripheral white blood cells and erythrocytes. SJL/J mice demonstrating clinical illness were given HRP or CF, in vivo or in situ, respectively.

Age-dependent antileukemic action and suppression of immune response by 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) in mice.

The antineoplastic activity of 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone) against murine leukemia P388 was found to be markedly reduced in 12- and 18-month-old mice as compared to young animals. The immune response against sheep red blood cells (SRBC), a T cell-dependent antigen, was also strongly diminished in tumor-free old mice and was further suppressed after ambazone treatment. Since the antileukemic effect of ambazone disappeared more or less in congenitally athymic nude mice, in neonatally thymectomized or silica-pretreated animals, it has been concluded that the action of the compound seems to be limited to young adult immunocompetent tumor-bearing hosts.

High voltage electron microscopic studies of endothelial cell tubular structures in the mouse blood-brain barrier following brain trauma.

High-voltage electron microscopy was applied to the study of endothelial cell (EC) transport of macromolecules in a murine model of blood-brain barrier injury to study the role of the EC canalicular system following brain insult. Semithick sections from mouse brains subjected to acute (2-3 h) mechanical trauma demonstrated permeation of intravenously injected horseradish peroxidase via tubular structures either (a) in the absence of lysosome-associated structures in close proximity, or (b) in association with lysosomes, dense bodies or multivesicular bodies. Our data suggest a dual-purposed system of tubules, one portion that supplies the metabolic requirements of the cell and another portion, suggested to be more limited, that opens up as a result of brain injury.

A 31 kilodalton beta-protein immunoreactive polypeptide in neuronal lipofuscin.

The beta-protein, a small fibrillar peptide which is the main constituent of the amyloid deposits in senile neuritic plaques and congophilic angiopathy derives by proteolytic cleavage from at least one of three large precursor proteins of 695 to 770 amino acids encoded by a gene on chromosome 21. In the brain the mRNA coding for these predicted proteins has been localized to neurons and non-neuronal cell types. Monoclonal antibodies raised to a synthetic peptide corresponding to residues 1 to 24 of the beta-protein do not only stain the amyloid deposits characteristic for Alzheimer neuropathology, but also neuronal lipofuscin.

Laboratory diagnostic tests for Alzheimer's disease.

Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT) is a neuro-degenerative disease which is characterized by the accumulation of paired helical filaments (PHF) in the form of neurofibrillary tangles and neuritic (senile) plaques in the brain. The clinical diagnosis of AD/SDAT is made by excluding other causes of dementia and is uncertain in 10-50% of the cases. The histopathological diagnosis of AD/SDAT can be made only on brain biopsy or after the patient has died on autopsied brain.