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B P Nathan

Publications and source records attributed to B P Nathan.

9 recordsLinked to original sources
PubMed2003

Regionally specific modulation of brain apolipoprotein E in the mouse during the estrous cycle and by exogenous 17beta estradiol.

Studies have suggested that 17beta estradiol (E2) can modify apolipoprotein E (apoE) expression. The current study determined if apoE protein varied in different regions of the mouse brain as a function of the estrous cycle and if E2 could increase apoE protein expression. In this study apoE concentration was lowest on estrus in the hippocampus, cingulate cortex and frontal cortex. In contrast, apoE concentration was highest on estrus in the olfactory bulb and cerebellum. There were no differences in the striatal apoE expression throughout the estrous cycle. Exogenous E2 significantly raised tissue levels of apoE in the olfactory bulb and cerebellum at 5 days after treatment. There was a slight, but nonsignificant increase in cortical expression of apoE and no change in striatum. Immunocytochemical localization studies found estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) in cortical neurons and glia. In the cerebellum and olfactory bulb, ERbeta was seen primarily in glia. ERalpha was not observed in the cerebellum and was rare in the olfactory bulb. Neither ERalpha nor ERbeta was seen in the striatum. Our data show regional differences in the production of apoE throughout the estrous cycle. In addition, exogenous E2 has regionally specific effects on apoE expression. Regional variability in apoE production appears to vary as a function of the estrogen receptor subtype.

Animals↗
PubMed2001

Apolipoprotein E is upregulated in olfactory bulb glia following peripheral receptor lesion in mice.

Apolipoprotein E (apoE), a lipid transporting protein, has been postulated to participate in nerve regeneration. To better clarify apoE function in the olfactory system, we evaluated the amount and distribution of apoE in the olfactory bulb following olfactory nerve lesion in mice. Olfactory nerve was lesioned in 2- to 4-month-old mice by intranasal irrigation with Triton X-100. Olfactory bulbs were collected at 0, 3, 7, 21, 42, and 56 days postlesion, and both apoE concentrations and apoE distribution were determined. ApoE levels, as determined by immunoblot analysis, were twofold greater than normal during nerve degeneration at 3 days. ApoE levels remained elevated by approximately 1.5 times normal levels at 7 through 21 days after injury and returned to baseline by 56 days. Immunocytochemical studies supported these observations. ApoE immunoreactivity was prominent on the olfactory nerve at 3 days after lesion and decreased to baseline levels at later time periods. Double-labeling immunocytochemical studies confirmed that both reactive astroglia and microglia produced detectable amounts of apoE following the lesion. Return of apoE expression to baseline paralleled measures of olfactory nerve maturation as measured by olfactory marker protein. These data suggest that apoE increases concurrent with nerve degeneration. ApoE may facilitate efficient regeneration perhaps by recycling lipids from degenerating fibers for use by growing axons. The association of apoE genotype with dementing illnesses may represent a diminished ability to support a lifetime of nerve regeneration.

Animals↗
PubMed2001

Volumetric and horseradish peroxidase tracing analysis of rat olfactory bulb following reversible olfactory nerve lesions.

Olfactory receptor neurons can regenerate from basal stem cells. Receptor neuron lesion causes degenerative changes in the olfactory bulb followed by regeneration as new olfactory receptor axons innervate the olfactory bulb. To our knowledge, parametric analyses of morphometric changes in the olfactory bulb during degeneration and regeneration do not exist except in abstract form. To better characterize olfactory bulb response, we performed morphometric analysis in rats following reversible olfactory nerve lesion with diethyldithiocarbamate. We also performed anterograde tracing of the olfactory nerve with wheatgerm agglutinin linked to horseradish peroxidase. Results of morphometry and tracing were complementary. The glomerular layer and external plexiform layer showed shrinkage of 45 and 26%, respectively, at 9 days. No significant shrinkage occurred in any other layer. Individual glomeruli shrank by 40-50% at 3 and 9 days following lesion. These data show that degenerative changes occur both in the glomeruli and transneuronally in the external plexiform layer. Olfactory nerve regeneration (identified by WGA-HRP transport) paralleled volumetric recovery. Recovery occurred first in ventral and lateral glomeruli between 9 and 16 days followed by recovery in medial and dorsal glomeruli. These data indicate substantial transynaptic degeneration in the olfactory bulb and a heretofore unrecognized gradient in olfactory nerve regeneration that can be used to systematically study recovery of a cortical structure.

Animals↗
PubMed1999

Apolipoprotein E immunoreactivity in human and mouse olfactory bulb.

We evaluated the distribution of apolipoprotein E (apoE) immunoreactivity in mouse and human olfactory bulbs. ApoE immunoreactivity was present in the olfactory nerve and around the glomeruli. Immunoreactivity was seen in somata that appeared to be glial. No neuronal staining was seen. The apoE immunoreactivity was also present in the mouse olfactory bulb subependymal layer. The specificity of immunoreactivity was confirmed with apoE-deficient mice (apoE gene knock-out mice, apoE KO) which did not display any immunoreactivity. The presence of apoE around glomeruli and nerve suggest that apoE is associated with the continuous degeneration and regeneration processes that occur in the olfactory nerve. Experimental manipulation of the olfactory nerve may be a useful technique to determine the functions of apoE in a well-defined neural system.

Adult↗
PubMed1996

Apolipoprotein E. Structure, function, and possible roles in Alzheimer's disease.

Apolipoprotein (apo) E is associated with the two characteristic neuropathologic lesions of Alzheimer's disease--extracellular neuritic plaques representing deposits of amyloid beta (A beta) peptide and intracellular neurofibrillary tangles representing filaments of a microtubule-associated protein called tau. Incubation of the apoE4 isoform with the A beta peptide in vitro results in the formation of a dense, stable network of very long monofibrils, while incubation of apoE3 with the A beta peptide results in the formation of a less dense, less stable network. The more complex nature of the plaques formed with the A beta peptide in the presence of apoE4 in vivo may impair the normal clearance process and enhance plaque formation. Alternatively or additionally, apoE may alter the cytoskeletal structure and function and, under certain conditions, may promote the formation of the neurofibrillary tangles. Our studies have demonstrated that apoE3 and apoE4 exert differential effects on neuronal growth (i.e., neurite extension and branching) in vitro. When combined with a source of lipid, apoE3 stimulated neurite extension in peripheral nervous system neurons (dorsal root ganglia), whereas apoE4 inhibited it. Similar results were obtained with central nervous system neurons (murine neuroblastoma Neuro-2a cells). Addition of free apoE3 or apoE4 without beta-VLDL had no effect on neurite outgrowth. There was also differential accumulation of apoE3 and apoE4 by the neuroblastoma cells: apoE3 accumulated within cell bodies and neurites to a greater extent than apoE4. Thus, apoE3 may facilitate cytoskeletal activity, whereas apoE4 may inhibit it, which would be detrimental during synaptic remodeling.

Alzheimer Disease↗
PubMed1995

Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth.

Previously, we demonstrated in cultured dorsal root ganglion neurons that, in the presence of beta-migrating very low density lipoproteins (beta-VLDL), apolipoprotein (apo) E4, but not apoE3, suppresses neurite outgrowth. In the current studies, murine neuroblastoma cells (Neuro-2a) were stably transfected with human apoE3 or apoE4 cDNA, and the effect on neurite outgrowth was examined. The stably transfected cells secreted nanogram quantities of apoE (44-89 ng/mg of cell protein in 48 h). In the absence of lipoproteins, neurite outgrowth was similar in the apoE3- and apoE4-secreting cells. The apoE4-secreting cells, when incubated with beta-VLDL, VLDL, cerebrospinal fluid lipoproteins (d < 1.21 g/ml), or with triglyceride/phospholipid (2.7:1 (w/w)) emulsions, showed a reduction in the number of neurites/cell, a decrease in neurite branching, and an inhibition of neurite extension, whereas in the apoE3-secreting cells in the presence of a lipid source, neurite extension was increased. Uptake of beta-VLDL occurred to a similar extent in both the apoE3- and apoE4-secreting cells. With low density lipoproteins or with dimyristoylphosphatidylcholine emulsions, either alone or complexed with cholesterol, no differential effect on neurite outgrowth was observed. A slight differential effect was observed with apoE-containing high density lipoproteins. The differential effect of apoE3 and apoE4 in the presence of beta-VLDL was blocked by incubation of the cells with heparinase and chlorate, with lactoferrin, or with receptor-associated protein, all of which prevent the uptake of lipoproteins by the low density lipoprotein receptor-related protein (LRP). The data suggest that the secreted and/or cell surface-bound apoE interact with the lipoproteins and facilitate their internalization via the heparan sulfate proteoglycan-LRP pathway. The mechanism by which apoE3 and apoE4 exert differential effects on neurite outgrowth remains speculative. However, the data suggest that apoE4, which has been shown to be associated with late onset familial and sporadic Alzheimer's disease, may inhibit neuronal remodeling and contribute to the progression of the disease.

Alzheimer Disease↗
PubMed1995

The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization.

Evidence is presented for the differential effects of two isoforms of apolipoprotein (apo) E, apoE3 and apoE4, on neurite outgrowth and on the cytoskeleton of neuronal cells (Neuro-2a) in culture. In the presence of a lipid source, apoE3 enhances and apoE4 inhibits neurite outgrowth. Immunocytochemical studies demonstrate that there is a higher concentration of apoE3 than apoE4 in both the cell bodies and neurites. Cells treated with apoE4 showed fewer microtubules and a greatly reduced ratio of polymerized to monomeric tubulin than did cells treated with apoE3. The effect of apoE4 on depolymerization of microtubules was shown by biochemical, immunocytochemical, and ultrastructural studies. The depolymerization of microtubules and the inhibition of neurite outgrowth associated with apoE4 suggest a mechanism whereby apoE4, which has been linked to the pathogenesis of Alzheimer's disease, may prevent normal neuronal remodeling from occurring later in life, when this neurodegenerative disorder develops.

Actins↗
PubMed1994

Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.

Apolipoprotein E4 (apoE4), one of the three common isoforms of apoE, has been implicated in Alzheimer's disease. The effects of apoE on neuronal growth were determined in cultures of dorsal root ganglion neurons. In the presence of beta-migrating very low density lipoproteins (beta-VLDL), apoE3 increased neurite outgrowth, whereas apoE4 decreased outgrowth. The effects of apoE3 or apoE4 in the presence of beta-VLDL were prevented by incubation with a monoclonal antibody to apoE or by reductive methylation of apoE, both of which block the ability of apoE to interact with lipoprotein receptors. The data suggest that receptor-mediated binding or internalization (or both) of apoE-enriched beta-VLDL leads to isoform-specific differences in interactions with cellular proteins that affect neurite outgrowth.

Animals↗