Showing papers by "John Q. Trojanowski published in 1994"

Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease.

Abstract: Ubiquitin-immunoreactive dystrophic neurites in the CA2/3 region of the hippocampus are characteristic of diffuse Lewy body disease (DLBD). The origin of dystrophic CA2/3 neurites is unknown, but their extent correlates with the number of cortical Lewy bodies (LBs). To examine the molecular composition of these lesions, hippocampal sections were obtained at postmortem from cases of DLBD, Parkinson's disease and Alzheimer's disease. The tissue samples were fixed in a variety of fixatives and immunostained with antibodies to ubiquitin, ubiquitin C-terminal hydrolase (PGP9.5), neurofilament protein subunits, tau protein, paired helical filaments and tyrosine hydroxylase (TH). In addition to being ubiquitin positive, both cortical LBs and CA2/3 dystrophic neurites were positive with a neurofilament monoclonal antibody (RM032) and PGP9.5; however, fewer lesions were detected with these antibodies compared to ubiquitin immunocyto-chemistry. The dystrophic CA2/3 neurites were not stained with antibodies to tau proteins, paired helical filaments or TH. Absence of TH immunoreactivity suggests that CA2/3 neuritic processes are not derived from brain stem dopaminergic afferents to the hippocampus. Since CA2/3 neurites are immunologically similar to cortical LB, the pathogenesis of these lesions may be similar. Characterization of dystrophic CA2/3 neurites and cortical LBs may clarify how these lesions contribute to the emergence of dementia in DLBD.

Aluminum modifies the properties of Alzheimer's disease PHF tau proteins in vivo and in vitro

Abstract: Hyperphosphorylated adult human CNS tau (PHF tau or A68) forms paired helical filaments (PHFs) in neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites associated with senile plaques (SPs) during the progression of Alzheimer9s disease (AD). While amyloid fibrils in SPs are composed of beta-amyloid (A beta), NFTs and SPs contain similar associated components such as ubiquitin, alpha 1- antichymotrypsin (ACT), apolipoprotein E (ApoE), heparan sulfate proteoglycans (HSPGs), and aluminum salts. Thus, SPs and NFTs may result from specific interactions between PHF tau, A beta, and these other components. In fact, intracerebral injections of PHF tau induce co-deposits of A beta, ACT, and ubiquitin (Shin et al., 1993). To examine this issue further, we probed interactions between PHF tau, aluminum salts, and other plaque and tangle components. We investigated in vivo interactions of PHF tau and aluminum chloride (AlCl3) with other plaque and tangle components by injecting PHF tau with and without AlCl3 into the rodent brain. PHF tau co-injected with AlCl3 formed aggregates that persisted much longer in the rat brain, and induced longer-lived co-deposits of A beta, ubiquitin, ACT, and ApoE than PHF tau alone. Injections of PHF tau with AlCl3 also induced neurons near the injection site to acquire PHF tau-like properties as monitored with antibodies (AT8, T3P, PHF1) that recognize defined PHF tau epitopes containing phosphoserine residues (Ser202, Ser396, Ser404). Injections of AlCl3 alone as well as injections of normal adult and fetal CNS tau, several different synthetic peptides, neurofilament proteins, ACT, HSPGs, or ApoE with and without AlCl3 failed to induce co-deposits of A beta or alter the immunoreactivity of tau in rodent neurons. To determine if aluminum salts interact directly and specifically with PHF tau in situ, we pretreated sections of AD hippocampus with 10 mM AlCl3 and then probed these sections by immunohistochemistry with antibodies to PHF tau as well as to a number of other plaque and tangle components. Preincubation of these sections with AlCl3 diminished PHF tau immunoreactivity in NFTs and SPs using the PHF tau-specific antibodies AT8, T3P, and PHF1, while the immunoreactivity of other plaque and tangle proteins (A beta, ubiquitin, ACT, HSPGs, ApoE) was not abolished. We also examined the effects of AlCl3 on PHF tau and normal adult human CNS tau in vitro. AlCl3 had no effect on normal adult human CNS tau, while increasing concentrations of AlCl3 (from 0.1 to 1.0 mM) induced PHF tau to aggregate at the top of the stacking gel, and at high concentrations (0.3 and 1.0 mM) of AlCl3, PHF tau completely failed to enter the gel. These studies suggest that aluminum binds to PHF tau, induces these proteins to aggregate, and retards their proteolysis. Further, since intracerebral injections of PHF tau with and without AlCl3 in rats appear uniquely capable of inducing co-deposits of a number of proteins found in authentic AD SPs and NFTs (including A beta, ubiquitin, ACT, and ApoE), we speculate that the contributions of PHF tau to plaque and tangle formation in AD may be modulated by aluminum.

Modulation of axon diameter and neurofilaments by hypomyelinating Schwann cells in transgenic mice.

Abstract: Studies of peripheral nerves in two different lines of hypomyelinating transgenic mice support the hypothesis that myelinating Schwann cells exert a significant influence on key biological properties of axons. The mice contain transgenes combining the peripheral myelin protein zero gene (P0) promoter and either the diphtheria toxin A chain gene product or the SV40 (simian virus 40) large T antigen. The consequences of peripheral nerve hypomyelination on axon diameter, neurofilament (NF) density, and NF phosphorylation were analyzed. The sciatic nerves of the P0 diphtheria toxin A transgenic mice (DT) evidenced the most severe hypomyelination, and this was associated with a dramatic decrease in NF phosphorylation plus a marked increase in NF density. In contrast, the sciatic nerves in the P0 SV40 large T antigen transgenic mice (SV40) were not as severely hypomyelinated and there was a milder decrease in NF phosphorylation plus a more modest increase in NF density. Further, the sciatic nerves in both lines evidenced a decrease in axonal caliber without any change in NF content. Taken together, these studies provide strong evidence indicating that myelinating Schwann cells exert a significant influence on axon caliber by modulating NF phosphorylation and NF packing density in the axons of peripheral nerves. Thus, key biological properties of axons are modulated by signals transmitted from myelinating Schwann cells to axons of peripheral nerves.

Cerebellar dysplasias in humans: development and possible relationship to glial and primitive neuroectodermal tumors of the cerebellar vermis.

Abstract: Cerebellar dysplasias are commonly found in the white matter and nodulus of the vermis in newborns and are particularly prominent in infants with trisomy 13-15 and trisomy 18 syndromes. Little is known of the developmental biology of these structures. We have studied the development of cerebellar dysplasias in human fetuses ranging from 15 to 32 weeks gestational age and from 11 days to 15 months postnatal. The expression of developmentally regulated neuronal and glial polypeptides was investigated by immunohistochemistry using a panel of extensively characterized monoclonal antibodies. Dysplasias were first observed at 15 weeks gestation as irregularly distributed, parenchymal or perivascular clusters of primitive cells in the inferior vermis. These cell clusters resembled primitive neuroepithelial cells or cells of the cerebellar external granule cell layer and they persisted into postnatal life. They retained the capacity to undergo cell division and were weakly reactive for the low affinity nerve growth factor receptor but were negative for all other neuronal or glial proteins at all gestational ages. At about 20 weeks gestation, cerebellar dysplasias become more complex with the appearance of ganglion cells which matured histologically and phenotypically in parallel with normal dentate neurons and Purkinje cells. These dysplasias often contained a prominent glial component which was identified by immunostaining for glial fibrillary acidic protein. Our findings suggest that midline cerebellar dysplasias are normal variants of development. Whether the mitotically active cells comprising these dysplasias are targets for neoplastic transformation into cerebellar primitive neuroectodermal tumors or other types of childhood tumors such as pilocytic astrocytomas or atypical teratoid/rhabdoid tumors remains speculative.

Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan

Abstract: The apolipoprotein E epsilon 4 allele has been associated with both familial and sporadic Alzheimer's disease (AD). Given its possible role in nerve repair and growth, it is plausible that apolipoprotein E may be a common denominator in the pathogenesis of several dementing diseases. Therefore, we investigated epsilon 4 frequencies in demented and nondemented alcoholics, as well as in patients with sporadic AD and controls in Japan. No significant differences in allele frequencies was found between demented and nondemented alcoholics and controls, while a significant association was demonstrated between AD and the epsilon 4 allele. These results support a specific role of epsilon 4 in the pathogenesis of AD, rather than a more general role for epsilon 4 in dementing illnesses.

In vivo and in vitro models of medulloblastomas and other primitive neuroectodermal brain tumors of childhood

Abstract: Recent advances in understanding the basic biology of the neoplastic cells that populate childhood primitive neuroectodermal tumors (PNET) of the central nervous system (CNS) underline several unique properties of these common pediatric brain neoplasms. For example, studies of posterior fossa cerebellar medulloblastomas (MB), a prototypical group of brain tumors that comprise the largest class of PNET, suggest that the molecular phenotype of subpopulations of neoplastic cells in MB partially recapitulates stages in the acquisition of the neuronal phenotype by normal developing human CNS progenitor cells. However, as reviewed here, it appears that the neoplastic cells in MB exhibit one or more molecular defects in the sequence of normal maturational events that enable CNS progenitor cells to exit the cell cycle, become committed to the neuronal lineage, and undergo terminal differentiation into fully mature, permanently postmitotic CNS neurons. Indeed, since PNET emerge almost exclusively in early childhood, the induction of PNET may result from genetic lesions that arise in developing CNS progenitor cells thereby preventing these neural precursors from executing normal programs of lineage commitment and differentiation in the CNS. Clarification of how lineage commitment and maturation in PNET comprised of neuron-like tumor cells deviate from normal CNS development may clarify how oncogenes and tumor suppressor genes exert their effects in a cell type specific manner at different stages in the normal maturation of CNS cells. Recently, a number of potentially effective in vitro and in vivo model systems of PNET have been developed. Since these model systems could facilitate efforts to elucidate mechanisms of neoplastic transformation and tumor progression in the CNS, we review, the potential utility of several recently described in vitro (e.g., MB cell lines) and in vivo (e.g., transgenic mice) experimental systems as models of authentic childhood CNS neoplasms.

Method of stabilizing microtubules

Abstract: A method of stabilizing microtubules which are destabilized due to insufficient levels of normal human tau protein is disclosed. The method comprises the steps of contacting a microtubule that is destablizing due to a deficiency in normal tau protein with an amount of taxol sufficient to stabilize microtubules.

Rat comprising straight filaments in its brain

Abstract: Methods of generating a rat having Aβ deposits in the brain of the rat by injecting an amount of human A68 protein sufficient to result in formation of the deposits and subsequently examining the rat for the formation of the deposits are disclosed. Rats characterized by the presence of Aβ deposits similar to those found in individuals with Alzheimer's disease are also disclosed. Methods of screening test compositions for prophylactic or therapeutic activity by generating a rat having Aβ deposits in its brain, treating the animal with the test composition and examining the animal for therapeutic or prophylactic effectiveness are also disclosed.