Biomedical subjects

Virginia Hovanesian

Publications and source records attributed to Virginia Hovanesian.

5 recordsLinked to original sources

PubMed2006

RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.

The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.

Aged↗

PubMed2006

Musashi1 antigen expression in human fetal germinal matrix development.

Musashi1 is a highly conserved protein found in neural progenitor cells. We examined the expression dynamics of Musashi1 in conjunction with other representative neural progenitor antigenic determinants (Ki-67 and nestin) during 8 different stages of the developing human fetal germinal matrix. Our results indicate that Musashi1 is a useful marker for immature cells in periventricular areas inhabited by stem cells, progenitor cells, and differentiating cells.

Brain↗

PubMed2006

Engineering mucosal RNA interference in vivo.

Mucosal surfaces serve as a gateway to disease. Here, we demonstrate that RNA interference can be used to manipulate mucosal gene expression in vivo. Using a murine model, we show that direct application of liposome-complexed siRNA mediates gene-specific silencing in cervicovaginal and rectal mucosa. A single vaginal or rectal administration of siRNA targeting hematopoietic or somatic cell gene products reduced corresponding mRNA levels by up to 90%. Using a murine model of inflammatory bowel disease, we found that the rectal application of siRNA targeting TNF-alpha led to relative mucosal resistance to experimental colitis. Liposomal siRNA formulations proved nontoxic, did not elicit a nonspecific interferon response, and provide a means for genetic engineering of mucosal surfaces in vivo.

Animals↗

PubMed2004

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone.

Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropin-releasing hormone (TRH). Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.

Animals↗

PubMed2003

Stress protein expression in the Alzheimer-diseased choroid plexus.

Abnormal patterns of stress protein expression are found in the cerebral cortex and hippocampus of Alzheimer (AD) subjects. In this study, expression of various stress proteins in the Alzheimer-diseased choroid plexus (CP) was assessed immunohistochemically. We observed decreased HO-1 immunoreactivity in the AD CP, commensurate with our earlier report of suppressed HO-1 protein levels in AD cerebrospinal fluid (Schipper et al., Neurology 54:1297-1304, 2000). Heat shock protein (HSP) 90 was up-regulated in the AD CP relative to controls. There was a trend towards increased expression of HSP60, a mitochondrial stress protein; this is compatible with mitochondrial pathology recently documented in AD CP. Up-regulation of HSP90, a steroid receptor chaperone, in the AD CP may indicate abnormal hormone receptor expression in this secretory tissue. Glucose-regulated protein (GRP) 78 and 94 immunostaining was diminished in AD CP, implicating possible derangements in glucose or calcium homeostasis. Oxidative stress, per se, is probably not responsible for our observations because: i) there were no noticeable differences in the expression of HSP 70, ubiquitin, and alpha-B crystallin in the AD CP; and ii) augmentation, rather than the noted suppression, of HO-1 immunoreactivity would have been expected.

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