ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo.

Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins.

Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice.

Heat shock-initiated apoptosis is accelerated and removal of damaged cells is delayed in the testis of clusterin/ApoJ knock-out mice.

The secretion and localization of clusterin in the testis has led to the hypothesis that clusterin plays a role in spermatogenesis. Furthermore, the association of clusterin with apoptosis, cellular injury, disease, and regression of nongonadal tissues has led to the hypothesis that clusterin acts to protect cells from apoptosis or may be involved in tissue remodeling. To investigate the role of clusterin in the testis, we analyzed clusterin knock-out (cluKO) mice to determine the impact of the absence of clusterin on spermatogenesis.

Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging.

Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium.

Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia.

Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking.

Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis.

Apolipoprotein J/clusterin (apoJ/clusterin), an intriguing protein with unknown function, is induced in myocarditis and numerous other inflammatory injuries. To test its ability to modify myosin-induced autoimmune myocarditis, we generated apoJ-deficient mice. ApoJ-deficient and wild-type mice exhibited similar initial onset of myocarditis, as evidenced by the induction of two early markers of the T cell-mediated immune response, MHC-II and TNF receptor p55.

Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration.

Lecithin:cholesteryl acyltransferase (LCAT) deficiency resulting from targeted disruption of the Lcat gene in the mouse is associated with dramatic decreases in HDL concentration and the accumulation of nascent HDL in the plasma. We examined whether LCAT deficiency in mice is associated with a concomitant decrease in two antioxidative enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In control Lcat (+/+) mice both these enzymes are transported on HDL.

Identification and immunohistochemical localization of protein precursors to human axillary odors in apocrine glands and secretions.

Objectives: To determine the cellular localization in male and female axillary tissue for apocrine secretion odor-binding proteins 1 (ASOB1) and 2 (ASOB2) and the electrophoretic pattern of female apocrine proteins and to begin characterization of the ASOB1 protein.

Design: Immunohistochemical techniques were used with biopsy samples from axillary tissue of male and female subjects. Immunological techniques and microsequencing were used to characterize several of the proteins in male and female apocrine secretions.

Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated.

Potent neurotoxicity is associated with both apolipoprotein E (apoE)-related synthetic peptides and the 22 kDa N-terminal thrombin-cleavage fragment of apoE. Furthermore, the E4 isoform of the 22 kDa fragment is significantly more toxic than the same fragment derived from the E3 isoform, suggesting the possibility of a direct role of apoE-associated neurotoxicity in the pathophysiology of Alzheimer's disease. In the present study, the potential role of cell surface receptors in mediating neurotoxicity was assessed by using a variety of agents that should block the heparin-binding and receptor-binding activity of apoE.

A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity.

A 22 kDa fragment of apoE containing a putative cytotoxi domain was identified in postmortem human brain tissue and fresh CSF. This fragment is apparently equivalent to the major apoE thrombin cleavage product. In vitro toxicity assays demonstrate that the corresponding fragment derived from recombinantly expressed human apoE is toxic to primary neurons in culture and that the E4-derived fragment is significantly more toxic than the fragment derived from the E3 isoform.

Apolipoprotein J/clusterin expression defines distinct stages of blastocyst implantation in the mouse uterus.

The endometrium is a dynamic tissue that responds to hormonal cues and growth factors to accommodate, regulate, and nurture developing embryos. To provide clues about the molecular mechanisms underlying the responsiveness of this tissue, we have begun to identify genes that are expressed at specific stages of early pregnancy. One such gene, apolipoprotein J (apoJ), encodes a secretory glycoprotein capable of binding lipids and membrane-active proteins.

Apolipoprotein J/clusterin induction in myocarditis: A localized response gene to myocardial injury.

The function of apolipoprotein J (apoJ) is unknown, but it has been hypothesized to be cytoprotective. In the normal heart, abundant apoJ mRNA and protein are expressed in atrial myocytes; no expression is detected in ventricular myocytes. To provide clues about the role of apoJ in the heart, the response of apoJ to heart disease, including three models of myocarditis and two models of in vivo pressure overload hypertrophy, were examined.

Transforming growth factor beta (TGF beta)-induced nuclear localization of apolipoprotein J/clusterin in epithelial cells.

Apolipoprotein J (apoJ)/clusterin was first identified as an 80 kDa secretory glycoprotein present in most body fluids. It has been implicated in a variety of physiological processes including cellular differentiation and apoptosis. We demonstrate here that in addition to the well characterized secreted form of the protein, there exists an intracellular, nuclear form of apoJ.

Understanding cardiac development through the perspective of gene regulation and gene manipulation.

Cardiovascular malformations affect about 1% of newborns, yet much remains to be learned about the pathogenesis of these defects. Advances in understanding some of the molecular events involved in regulating cardiac morphogenesis are providing a new perspective with which to approach complex issues and questions related to congenital heart disease. More important, this new information provides not only unique opportunities for developing specific experimental models of congenital heart disease through direct genetic manipulation but also the basis for developing ways of therapeutically manipulating cardiac gene expression for some form of heart disease.

Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity.

Apoliprotein E (apoE) is a potent suppressor of interleukin 2- (IL2-) dependent T lymphocyte proliferation. In this study, we have used a range of monomeric and dimeric peptides encompassing amino acids 130-169 in human apoE to locate a region with both cytostatic and cytotoxic effects on IL2-dependent T lymphocytes. Monomeric peptides representing residues 130-149 or 130-155 inhibited the proliferation of the cells without causing loss of cell viability.

Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin.

Glycoprotein 330 (gp330) is a member of a family of endocytic receptors related to the low density lipoprotein receptor. gp330 has previously been shown to bind a number of ligands in common with its family member, the low density lipoprotein receptor-related protein (LRP). To identify ligands specific for gp330 and relevant to its localization on epithelia such as in the mammary gland, gp330-Sepharose affinity chromatography was performed.

Expression of apolipoprotein J in the uterus is associated with tissue remodeling.

The endometrium is a dynamic tissue that, in response to hormonal cues, undergoes cycles of growth and involution. Extracellular factors required for this remodeling are poorly understood. The potential role in endometrial turnover of apolipoprotein J (apoJ), a secretory glycoprotein that can bind lipids and membrane-active proteins, is proposed on the basis of its spatial and temporal patterns of expression during normal cycling, after ovariectomy, and in response to hormone manipulation.

Local synthesis of apolipoprotein J in the eye.

Apolipoprotein J (apoJ), a secretory glycoprotein known to transport lipids and to regulate terminal complement function, is present in the human eye in both aqueous and vitreous, as well as in the retina. Ocular apoJ is the product of local synthesis, rather than plasma contamination, as demonstrated by its distinct structural properties and the presence of abundant apoJ mRNA in retina and retina pigment epithelium. ApoJ mRNA is also present in mouse eye, with a developmentally regulated pattern of expression.

Apolipoprotein E restricts interleukin-dependent T lymphocyte proliferation at the G1A/G1B boundary.

Apolipoprotein E (apoE), a lipid transport protein important in cholesterol homeostasis, inhibits the proliferation of interleukin-dependent lymphocytes. Growth factor-responsive cells are blocked in the G1A phase of the cell cycle. Suppression by apoE is independent of growth factor, as evidenced by the fact that interleukin-2 (IL2)- and IL4-dependent proliferation of HT-2 T lymphocytes is equally inhibited.

Apolipoprotein E inhibition of proliferation of mitogen-activated T lymphocytes: production of interleukin 2 with reduced biological activity.

Apolipoprotein E (apoE), but not apoAI or apoCIII, suppresses mitogen-activated T lymphocyte proliferation, independent of the type of activation signal. Both CD4 and CD8 T cells are inhibited. ApoE inhibits T cell proliferation, in part, by reducing the production of bioactive interleukin 2 (IL2).

Temporally and spatially restricted expression of apolipoprotein J in the developing heart defines discrete stages of valve morphogenesis.

During cardiac valve morphogenesis, a series of interactions between the mesodermal-derived myocardium and the overlying endothelium lead to condensed leaflet structure formation. At the atrioventricular (AV) canal, endocardial cells are transformed by specialized underlying myocardial cells into endocardial cushions, and then remodeled into mitral and tricuspid valves. Aortic and pulmonary valves develop by a similar mechanism in the primitive outflow tract.

Neurite degeneration elicited by apolipoprotein E peptides.

Apolipoprotein E (apoE) has been localized to the neurofibrillary tangles and beta-amyloid-containing plaques found in the cortex of patients with Alzheimer's disease (AD) (14, 28), suggesting that apoE may play a role in this disorder. Recently, synthetic peptides containing a sequence within apoE (amino acids 141-155) were found to be cytotoxic to T lymphocytes in culture. In the present study, tandem presentation of the apoE sequence E141-155, as well as longer monomeric peptides that include this domain, was found to cause extensive and specific degeneration of neurites from embryonic chick sympathetic ganglia in vitro.

Apolipoprotein J is associated with paraoxonase in human plasma.

Apolipoprotein J (apoJ)-containing high-density lipoproteins (HDL), isolated from human plasma by immunoaffinity chromatography, are associated with apoAI and a protein of approximately 44 kDa. In order to advance our understanding of apoJ's role in the vasculature, a comprehensive investigation was performed to identify and characterize this 44-kDa protein and to study its interaction with apoJ. The 44-kDa protein, a monomeric glycoyslated polypeptide, was identified by N-terminal sequencing as serum paraoxonase.