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Biomedical subjects

G Perry

Publications and source records attributed to G Perry.

At least 235 records · Page 13Linked to original sources
PubMed1989

Soluble derivatives of the beta amyloid protein precursor of Alzheimer's disease are labeled by antisera to the beta amyloid protein.

The amyloid deposited in Alzheimer's disease (AD) is composed primarily of a 39-42 residue polypeptide (beta AP) that is derived from a larger beta amyloid protein precursor (beta APP). In previous studies, we and others identified full-length, membrane-associated forms of the beta APP and showed that these forms are processed into soluble derivatives that lack the carboxyl-terminus of the full-length forms. In this report, we demonstrate that the soluble approximately 125 and approximately 105 kDa forms of the beta APP found in human cerebrospinal fluid are specifically labeled by several different antisera to the beta AP. This finding indicates that both soluble derivatives contain all or part of the beta AP sequence, and it suggests that one or both of these forms may be the immediate precursor of the amyloid deposited in AD.

Alzheimer Disease↗
PubMed1989

Tau-reactive neurofibrillary tangles in cerebellar cortex from patients with Alzheimer's disease.

In 4 cases of Alzheimer's disease (AD) a tau antiserum immunostained thin, round or flame-shaped profiles disposed around the nuclei of the cerebellar fusiform-type Golgi cells. In adjacent sections either a Bodian silver method or Congo red failed to reveal any abnormal structures. Since normal tau immunoreactivity is located on axons and is absent in formalin-fixed tissue, the tau-reactive profiles are likely to correspond to small masses of abnormal filaments, antigenically similar to those composing neurofibrillary tangles (NFT). This observation indicates that in AD the NFT formation is more diffuse than that showed with conventional histological methods.

Aged↗
PubMed1989

The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from those of idiopathic Parkinson disease.

The antigenic components of Lewy bodies in the cerebral cortex and substantia nigra in 5 cases of diffuse Lewy body disease were examined by immunocytochemistry, using antibodies to neurofilaments (in the phosphorylated or non-phosphorylated forms); to ubiquitin; to the microtubule-associated proteins MAP1, MAP2 and tau; to isolated Alzheimer paired helical filaments, and to tubulin, in the tyrosinated and non-tyrosinated forms. Immunoreactivity with antibodies to cytoskeletal components was identical to that previously described for Lewy bodies of idiopathic Parkinson disease, with the exception that the inclusions of diffuse Lewy body disease (in both cortex and substantia nigra) were stained by an antibody to tau protein. Our findings indicate that although the inclusions found in diffuse Lewy body disease share structural and epitopic features with the inclusions of idiopathic Parkinson disease, they also have distinguishing characteristics (in addition to the differing neuronal populations involved). Also, they suggest that although the inclusions in both conditions appear similar, they probably have different pathogenetic origins.

Aged↗
PubMed1989

Immunoaffinity demonstration that paired helical filaments of Alzheimer disease share epitopes with neurofilaments, MAP2 and tau.

Identification of the neuronal components incorporated into the neurofibrillary tangles of Alzheimer disease has primarily been derived from immunocytochemical procedures. Previous antibody studies have been able to directly determine the shared epitopes of known neuronal proteins with neurofibrillary tangles (NFT) only when the appropriate monoclonal antibodies were available. In this study, we use an immuno-affinity purification protocol to directly determine the properties of the epitopes recognized by two antisera which recognize NFT. Characterization of the purified antibodies demonstrates that NFT share epitopes with the two heavier neurofilament subunits. NFH and NFM, as well as MAP2 and tau. Further, this method indicates that the epitopes shared with neurofilaments and tau are distinct from each other.

Alzheimer Disease↗
PubMed1989

The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition.

The structural changes of Alzheimer's disease (AD) include a widespread alteration of neuronal cell processes in addition to senile plaques and neurofibrillary tangles. Since the antigenic characteristics of these abnormal neurites are similar to those of the abnormal neurites associated with the senile plaques, the question has been raised as to whether the widespread neuritic alteration is secondary to the deposition of amyloid. To answer this question, we examined brains from 2 subjects with a longer-lasting form of subacute sclerosing panencephalitis (SSPE) characterized by the presence of numerous neurofibrillary tangles but no senile plaques, 3 subjects with AD, and 2 age-matched controls. Light and electron immunocytochemical analyses revealed that abnormal neurites are present diffusely in SSPE cerebral cortex in the absence of amyloid deposits. These abnormal neurites were qualitatively identical to the widespread abnormal neurites of AD. The abnormal neurites, in contrast to the neurites of control brains, immunoreacted with antibodies to tau and ubiquitin. These distinctive antigenic features were due to the presence in these abnormal neurites of straight filaments, 14 to 16 nm in diameter, mixed with a few paired helical filaments. The spatial distribution of the widespread neuritic alteration correlated with that of neurofibrillary tangles in both conditions, but not with that of senile plaques in AD. The present findings demonstrate that a diffuse alteration of neurites similar to that present in AD takes place independently of the deposition of amyloid in SSPE, and they are consistent with the hypothesis that in AD, also, this alteration is not secondary to the deposition of amyloid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

A new type of neuronal cytoplasmic inclusion: histological, ultrastructural, and immunocytochemical studies.

A novel type of non-viral cytoplasmic inclusion is described, which was seen in virtually every neuron in the brain and spinal cord of a child with a presumed metabolic disorder whose clinical picture and CNS pathology were compatible with Leigh Syndrome. The ovoid to round inclusions were sharply demarcated, measuring up to 11 microns in diameter. They showed no distinctive staining with a battery of routine histological techniques. The ultrastructural features are unique, comprising non-membrane-bounded aggregates of randomly oriented plate-like structures with parallel linear densities depicting a periodicity of 11-16 nm. Immunocytochemical studies revealed strong staining with antisera to tropomyosin and weaker staining with antisera to actin. There was no reactivity with antibodies against neurofilaments, microtubules and their associated proteins, paired helical filaments, ubiquitin, vinculin or alpha-actinin. It is postulated that the metabolic disorder resulted in a neurodegenerative condition which manifested pathologically with lesions compatible with those of Leigh Syndrome. Associated with the condition was the discrete accumulation of cytoplasmic proteinaceous components, including tropomyosin, in the form of neuronal cytoplasmic inclusions possibly resulting from an alteration of the neuronal cytoskeleton.

Brain Diseases, Metabolic↗
PubMed1989

Immunochemical properties of ubiquitin conjugates in the paired helical filaments of Alzheimer disease.

Immunocytochemical and peptide sequencing studies indicate that the regulatory protein ubiquitin (Ub) is incorporated into the paired helical filaments (PHF) of Alzheimer disease. In this study, we showed that some antibodies raised to PHF recognize epitopes of Ub. Analysis of the Ub sequences recognized by the antibodies raised to PHF, along with the known specificity of several monoclonal antibodies raised to artificial Ub conjugates, indicates the immunochemical representation of Ub residues 34-76 in PHF. The Ub epitopes recognized by antibodies raised to PHF are distinct from those recognized by antibodies raised to artificial Ub conjugates in two respects. First, antibodies that are raised to PHF and that recognize Ub react with PHF equally, whether denatured or not, whereas those raised to artificial Ub conjugates show greater reaction after denaturation. Second, mapping of the epitopes recognized by two monoclonal antibodies to PHF onto Ub indicates a distinction in the Ub residues recognized, compared with monoclonal antibodies raised to artificial Ub conjugates. The proximity of their epitopes to the site of conjugation, as well as their affinity for PHF polypeptides, suggests that the PHF antibodies that recognize Ub may be directed specifically to Ub epitopes defined by the protein conjugated to Ub.

Alzheimer Disease↗
PubMed1989

Selective presence of ubiquitin in intracellular inclusions.

The authors have shown previously that ubiquitin, a protein involved in the degradation of short-lived and abnormal proteins, is present in several cytoplasmic inclusions of neurons. This study used a library of antibodies to ubiquitin and immunohistochemically examined for the presence of ubiquitin in nonviral intracytoplasmic inclusions that form in different cell types under various pathologic conditions. Membrane-bound lysosomal and nonlysosomal inclusions such as those of storage disease, Russell bodies, alpha-1-antitrypsin and alpha-fetoprotein as well as nonmembrane-bound inclusions were examined. Ubiquitin epitopes were detected in some of the nonmembrane-bound inclusions only. The ubiquitin-containing inclusions were the Rosenthal fibers, Mallory bodies, Crooke bodies, Lafora bodies, amyloid bodies, and the giant axons of giant axonal neuropathy. Nemaline bodies and the inclusions of juvenile digital fibromatosis, both of which contain actin and actinbinding proteins, did not show immunoreaction. These findings, as well as those of the previous study, show that the presence of ubiquitin in cellular inclusions is selective. The ubiquitin-containing inclusions are not membrane bound; they are fibrillary and most contain also intermediate filament-related proteins. The role of ubiquitin in the formation of these inclusions remains to be elucidated.

Cell Nucleus↗
PubMed1989

Immunolocalization of the amyloid precursor protein within the senile plaque.

The isolation and sequencing of three transcripts for the precursor of the cerebral amyloid of Alzheimer disease have greatly facilitated understanding the relationship of the amyloid precursor protein (APP) to its 42 amino acid residue fragment (beta-protein or A4) which composes amyloid fibrils. In this study, we have used the 695 amino acid residue sequence described by Kang and co-workers to prepare antisera to synthetic peptides corresponding to various regions of APP in order to identify localized concentrations of this protein in cerebral cortex in cases of Alzheimer disease. We found that antisera to APP regions outside those of the amyloidogenic beta protein recognize diffuse non-congophilic plaques. While these antisera did not recognize the congophilic senile plaque core, they did recognize a halo surrounding them. Interestingly, cell processes were often identified in this halo region. In contrast, those antisera raised to sequences contained within beta-protein recognized both congophilic amyloid cores as well as non-congophilic diffuse plaques. Our findings suggest that accumulation of APP precedes development of and probably defines the senile plaque and the site of APP processing.

Alzheimer Disease↗
PubMed1989

Neurochemistry of dementia: establishing the links.

Neurochemical research in dementia needs to move beyond descriptive inventories of neurotransmitter systems affected in the specific disorders and to link to molecular studies of mechanism and clinical studies of cognition. New advances in Alzheimer's Disease (AD), Huntington's Disease (HD), and Parkinson's Disease (PD) are being guided by models of how nerve cells die in these disorders. Theories of pathophysiology which address the cellular level need to explain the selective vulnerability of neuronal populations in the different diseases. Clinically, the importance of neurochemical studies will be increased by understanding the bridges between neural and cognitive processes. Clinicians are concerned about the nosology of dementias, diagnostic tests, and more effective therapies. The value of neurochemical studies will be enhanced to the extent that they can contribute to understanding and modifying the clinical phenomenology of these disorders. In this paper, we will briefly review what is known about the neurochemistry of dementia but focus most of our attention on establishing the linkage between this level of description and the levels of description which are either "downstream" (molecular biology) or "upstream" (cognition) in terms of a reductionistic conception of understanding the disease process. We will explore how understanding neurochemistry relates to our understanding of disease mechanism and what constraints neurochemical studies place on understanding clinical aspects of disease. We will conclude by briefly discussing some of the problems with our current understanding of the neurochemistry of dementia and how we can address those problems in the future.

Alzheimer Disease↗
PubMed1989

Alteration of neuritic cytoarchitecture in Alzheimer disease.

Individuals afflicted with Alzheimer disease (AD) demonstrate two prominent brain structural alterations: senile plaques and neurofibrillary tangles (NFT) (Selkoe, 1986). Not appreciated until recently is a third quantitatively significant structure, the dystrophic neurite. Many of these altered neurites are focally associated with amyloid deposits, and together they comprise the senile plaque. However, the great majority of the abnormal neurites in AD are independent of senile plaques (Braak, et al., 1986). Recent advances have yielded considerable information on the chemical nature of the extracellular amyloid (Kang, et al., 1987; Tanzi, et al., 1988) which comprises the central portion of the senile plaque, but there is much yet to be unraveled concerning both the nature of NFT and the relationship between senile plaques and NFT (Selkoe, 1987). While the NFT is principally comprised of 20 nm helically wound filaments, descriptively termed paired helical filaments (PHF) (Kidd, 1963; Wisniewski, et al., 1976) occasionally 12-15 nm straight filaments are also present (Perry, et al., 1987c). We have found that the predominant filaments in dystrophic neurites of AD are straight filaments which are morphologically indistinguishable from those found within NFT. The abnormal neuritic filaments and PHF share microtubule associated protein, tau, and ubiquitin immunoreactivity. The prevalence of altered neurites suggests that reorganization of neuritic cytoarchitecture in AD, as demonstrated by the formation of abnormal polymers structurally, and by inference functionally distinct from the normal cytoskeleton, may constitute a more important part of the cytopathological change of AD than previously appreciated.

Alzheimer Disease↗
PubMed1988

The amyloid percursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types.

The vascular and parenchymal amyloid deposits in Alzheimer disease (AD), normal aging and Down syndrome are mainly composed of a 4 kDa polypeptide (A4), which derives from a larger precursor protein (APP). There is evidence that APP is a transmembrane glycoprotein present in most tissues, but the characteristics of APP in intact cells are not yet known. In order to investigate this issue, we examined the immunoreactivity of fibroblasts of human and nonhuman cell lines with antisera raised to synthetic peptides corresponding to A4 and to two other domains of the APP. All three antisera recognized a 130 kDa polypeptide (APP-130) in immunoblots from all cell lines. In fibroblasts, an additional polypeptide of 228 kDa (APP-228) was recognized by the antiserum to A4. In immunoblots of two dimensional gels, APP-130 showed a pI of 6.2, while APP-228 failed to focus in the pH range of 4.7-7.0. Sequential extractions of cells with buffer and with Triton X-100 indicate that APP-130 is extractable with nonionic detergents at high ionic strength, whereas 228 kDa APP is a cystolic component. Immunofluorescence staining is consistent with an intracellular perinuclear and plasma membrane localization. It is concluded that APP-130 and APP-228 are two forms of the APP which result from extensive posttranslational modifications of a smaller original gene product. It is likely that APP undergoes similar posttranslational modifications in different cell types.

Alzheimer Disease↗
PubMed1988

Paramyosin and actin in schistosomal teguments.

Schistosomes are blood-dwelling trematode parasites that infect 200 million people in developing countries. The critical role served by the tegument in immune evasion and parasite homeostasis suggests that a detailed knowledge of tegumental components would be helpful in the design of new drugs and the production of vaccines. We demonstrate here, by immunoelectron microscopy, that the cytoskeletal proteins actin and paramyosin are organized into major tegumental structures of Schistosoma mansoni. The surface spines are composed of paracrystalline arrays of actin filaments. Actin is also present in areas recovering from damage, implying an important role for this structural protein in tegumental repair. Paramyosin exists predominantly in the tegument in a non-filamentous form, the membrane-bounded elongate bodies. The localization of this protein to the tegument of the parasite is the likely basis for resistance to S. mansoni observed in mice immunized with paramyosin (refs 1, 2 and T. P. Flanigen et al., in preparation).

Actins↗
PubMed1988

Influence of neuronal location on antigenic properties of neurofibrillary tangles.

We quantitatively assessed the antigenic properties of the neurofibrillary tangles (NFT) located in neurons of the tegmental nuclei of the pontine raphe in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). These properties were then compared with those of NFT of AD located in hippocampal neurons. Antibodies known to react with cortical NFT of AD were used to stain sections from PSP, AD, and control cases. The reaction with the straight filaments of NFT of PSP and with the paired helical filaments of pontine NFT of AD was ascertained by immunoelectron microscopy. The results show that, despite the ultrastructural difference, straight filaments in NFT of PSP and paired helical filaments in NFT of AD share antigenic properties when they are located in the same neuronal population. In contrast, paired helical filaments located in the cerebral cortex are antigenically different from those in pontine nuclei. Location, more than structure, may play a role as determinant of antigenic properties in straight filaments of PSP and paired helical filaments of AD.

Aged↗