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Jonathan D Smith

Publications and source records attributed to Jonathan D Smith.

32 records · Page 2Linked to original sources
PubMed2004

Aging, gender and APOE isotype modulate metabolism of Alzheimer's Abeta peptides and F-isoprostanes in the absence of detectable amyloid deposits.

Aging and apolipoprotein E (APOE) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by-products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid beta (Abeta) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOEepsilon3 or human APOEepsilon4 alleles]. Aging-, gender-, and APOE-genotype-dependent changes were observed for endogenous mouse brain Abeta40 and Abeta42 peptides. Levels of the oxidized lipid F2-isoprostane (F2-isoPs) in the brains of the same animals as those used for the Abeta analyses revealed aging- and gender-dependent changes in APOE KO and in human APOEepsilon4 transgenic KO mice. Human APOEepsilon3 transgenic KO mice did not exhibit aging- or gender-dependent increases in F2-isoPs. In general, the changes in the levels of brain F2-isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Abeta levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging-dependent, APOE-genotype-sensitive rise in murine brain Abeta levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOEepsilon3, but not human APOEepsilon4, can apparently prevent the aging-dependent rise in murine brain Abeta levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Abeta/F2-isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F2-isoPs can stimulate Abeta generation and aggregation.

Aging↗
PubMed2004

Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease.

In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO(2)Tyr) and myeloperoxidase (MPO), a protein that catalyzes generation of nitrating oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident cardiac events. We now show both that apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and apoA-I results in selective inhibition in ABCA1-dependent cholesterol efflux from macrophages. Dramatic selective enrichment in NO(2)Tyr and chlorotyrosine (ClTyr) content within apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the NO(2)Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO(2)Tyr and ClTyr contents of the lipoprotein are each significantly associated with diminished ABCA1-dependent cholesterol efflux capacity of the lipoprotein. MPO as a likely mechanism for oxidative modification of apoA-I in vivo is apparently facilitated by MPO binding to apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human atheroma, and identification of a probable contact site between the apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for apoA-I as a selective target for MPO-catalyzed oxidative modification in human atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.

ATP Binding Cassette Transporter 1↗
PubMed2004

Drug discovery: estrogen-related compounds in mouse models of Alzheimer's disease.

Despite promising epidemiological studies that showed a decreased incidence of Alzheimer disease (AD) in women who used hormone replacement therapy (HRT), the results of the recently released Women's Health Initiative Memory Study has dampened any enthusiasm for the use of HRT in women to prevent or delay the onset of AD. In this position paper, we review these data, along with our own--using estrogens in a transgenic mouse model of AD--and introduce our current working hypothesis and research.

Alzheimer Disease↗
PubMed2003

In silico quantitative trait locus map for atherosclerosis susceptibility in apolipoprotein E-deficient mice.

OBJECTIVE: Atherosclerosis susceptibility is a genetic trait that varies between mouse strains. The goal of this study was to use a public mouse single nucleotide polymorphism (SNP) database to define the genetic loci that are associated with this trait, without the need to perform strain intercrosses that are normally required to obtain these loci. METHODS AND RESULTS: Apolipoprotein E (apoE)-deficient mice on 6 inbred genetic backgrounds were compared for atherosclerosis lesion size in the aortic root in 2 independent studies. After normalization to the C57BL/6 strain that was used in both studies, lesion areas were found in the following rank order: DBA/2J>C57BL/6>129/SV-ter>AKR/J approximately BALB/cByJ approximately C3H/HeJ. The log lesion difference in phenotypes between each of the 15 heterologous strain pairs was determined. A mouse SNP database was then used to calculate the genetic differences between the 15 strain pairs in partially overlapping 30-cM bins across the mouse genome. Correlation analyses were preformed to analyze the genetic and phenotypic differences among the strain pairs for each genetic region. The genetic regions with the highest correlations define the in silico quantitative trait loci (QTL) associated with the atherosclerosis phenotype. Five in silico atherosclerosis QTL were identified on chromosomes 1, 10, 14, 15, and 18. The loci on chromosomes 1, 10, 14, and 18 overlap with suggestive atherosclerosis QTL identified through analyses of an F(2) cohort derived from apoE-deficient mice on the C57BL/6 and FVB/N strains. CONCLUSIONS: The 5 identified in silico QTL are candidates for further study to confirm the presence and identity of atherosclerosis susceptibility genes within these loci.

Animals↗
PubMed2003

Potential use of estrogen-like drugs for the prevention of Alzheimer's disease.

Prior epidemiological studies have shown decreased incidence of Alzheimer's disease among women who were long-term users of hormone replacement therapy. In vitro studies have shown that estrogens possess antioxidant activity, protect cells from the cytotoxic effect of beta-amyloid peptides, and decrease the amyloidogenic processing of the amyloid precursor protein. Animal studies have shown that estrogens promote neuronal plasticity and lead to decreased levels of cerebral beta-amyloid peptide accumulation via decreased amyloidogenic processing of the amyloid precursor protein. Recently, a randomized double-blind placebo-controlled study of the effects of estrogen plus progestin treatment in women over 65 years of age found that this treatment was associated with increased incidence of probable dementia. It is not known whether this combination of hormones or the late age at which the therapy was administered was responsible for the adverse outcome.

Alzheimer Disease↗
PubMed2003

Safe and effective method for chronic 17beta-estradiol administration to mice.

Supraphysiological 17beta-estradiol treatment administered via subcutaneous pellets is commonly used in mice. However, despite its efficacy in eliciting a uterotrophic response, we demonstrate that this regimen also was associated with urine retention, hydronephrosis, and ultimately premature death. To determine a safer yet still effective method to chronically treat mice with 17beta-estradiol, we initiated a placebo-controlled study to treat ovariectomized C57BL/6J mice for 6 weeks with various doses of 17beta-estradiol administered either in their drinking water (0.3 to 1000 nM) or via pellets (0.72 mg or 1.7 mg). Uterine weights demonstrated a dose-dependent effect of 17beta-estradiol administered either orally or via pellets; however, the pellet treatments resulted in urine retention. Treatment with either 200 or 1000 nM 17beta-estradiol in the drinking water yielded physiological and supraphysiological uterotrophic responses, respectively, without urine retention, providing safe, effective, and economical ways to treat mice chronically with 17beta-estradiol.

Animals↗
PubMed2002

Evaluation of the role of phosphatidylserine translocase activity in ABCA1-mediated lipid efflux.

The following two theories for the mechanism of ABCA1 in lipid efflux to apolipoprotein acceptors have been proposed: 1) that ABCA1 directly binds the apolipoprotein ligand and then facilitates lipid efflux and 2) that ABCA1 acts as a phosphatidylserine (PS) translocase, increasing PS levels in the plasma membrane exofacial leaflet, and that this is sufficient to facilitate apolipoprotein binding and lipid assembly. Upon induction of ABCA1 in RAW264.7 cells by cAMP analogues there was a moderate increase in cell surface PS as detected by annexin V binding, whereas apoAI binding was increased more robustly. Apoptosis induced large increases in annexin V and apoAI binding; however, apoptotic cells did not efflux lipids to apoAI. Annexin V did not act as a cholesterol acceptor, and it did not compete for the cholesterol acceptor or cell binding activity of apoAI. ApoAI binds to ABCA1-expressing cells, and with incubation at 37 degrees C apoAI is co-localized within the cells in ABCA1-containing endosomes. Fluorescent recovery after photobleaching demonstrated that apoAI bound to ABCA1-expressing cells was relatively immobile, suggesting that it was bound either directly or indirectly to an integral membrane protein. Although ABCA1 induction was associated with a small increase in cell surface PS, these results argue against the notion that this cell surface PS is sufficient to mediate cellular apoAI binding and lipid efflux.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Apolipoproteins and aging: emerging mechanisms.

One of the goals of modern medicine is to foster successful aging. In order to age successfully, one must accomplish two things: first, survive; and second, survive with good health and a sharp mind. In this discussion of apolipoproteins and aging, the focus will be on apolipoprotein E (apoE), a protein with three common isoforms, which has a large impact on longevity and successful aging. One variant of apoE (E4) is associated with increased risk for heart disease, stroke and Alzheimer's disease (AD). In addition, some of the potential mechanisms for the observed effects of apoE on aging will be discussed.

Aging↗
PubMed2002

A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.

Animals↗
PubMed2002

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.

Alzheimer Disease↗
PubMed2002

The murine macrophage apoB-48 receptor gene (Apob-48r): homology to the human receptor.

Previously we cloned the human macrophage apolipoprotein B-48 receptor (ApoB-48R) and documented its expression in human atherosclerotic foam cells (1). Now we have identified and characterized the murine macrophage apob-48r cDNA gene sequence and its chromosomal location. The cDNA (3,615 bp) -deduced amino acid (aa) sequence (942 aa) is approximately 45% identical to the human macrophage APOB-48R, but not to other known gene families. The murine Apob-48r gene, like the human APOB-48R gene, consists of four exons interrupted by three small introns and is syntenically located on chromosome 7. Functionally significant conserved domains include an N-terminal hydrophobic domain, a glycosaminoglycan attachment site, an N-glycosylation site, and an ExxxLL internalization motif C-terminal to the putative internal transmembrane domain. Two conserved coiled-coil domains are likely involved in the spontaneous homodimerization that generates the active dimeric ligand binding species (mouse, approximately 190 kDa; human, approximately 200 kDa). Transfection of the murine apoB-48R into Chinese hamster ovary cells (CHOs) confers apoB-48R function: rapid, high-affinity, specific uptake of known triglyceride-rich lipoprotein ligands of the apoB-48R and, of note, uptake of the cholesteryl ester-rich apoB-48-containing very low density lipoproteins that accumulate in atherosclerosis-prone apoE-deficient mice. Uptake of these ligands by murine apoB-48R-transfected CHOs causes saturable, visible cellular triglyceride and cholesterol accumulation in vitro that resemble foam cells of atherosclerotic lesions. In aggregate, the data presented here and that previously published suggest that the apoE-independent murine apoB-48R pathway may contribute to the spontaneous development of atherosclerotic lesions rich in macrophage-derived foam cells observed in apoE-deficient mice, a murine model of human atherosclerosis.

Amino Acid Sequence↗
PubMed2002

Human cerebrospinal fluid apolipoprotein E isoforms are apparently inefficient at complexing with synthetic Alzheimer's amyloid-[beta] peptide (A[beta] 1-40 ) in vitro.

BACKGROUND: Variation at the apolipoprotein E locus on chromosome 19 plays a role in more cases of Alzheimer's disease than does any other identified genetic determinant. We have previously reported the isoform-specific interaction of native human apolipoprotein E (APOE, gene; apoE, protein) epsilon 3 with the amyloid-ss peptide, Ass(1-40), the major component of the cerebral amyloid deposits that appear to cause Alzheimer's disease. MATERIALS AND METHODS: In order to investigate the apoE: A beta interaction further, a modified assay was developed based on co-immunoprecipitation of the complex using an anti-apoE antibody (anti-apoE IP assay). RESULTS: Application of this assay demonstrated that the interaction of Ass(1-40) and apoE can be distinguished into two types: sodium dodecyl sulfate (SDS) -resistant and SDS-releasable. The SDS-resistant interaction between epsilon;3 and Ass(1-40) is apparently maximal at an Ass(1-40) concentration of approximately 75 micro M, and an Ass(1-40) /epsilon 3 molar ratio of about 250:1. The major apoE-isoform-specific difference in interaction with Ass(1-40) is the ability of Ass(1-40) to form SDS- resistant complexes with epsilon 3 but not with epsilon 4. Using the anti-apoE co-IP assay, we found that human cerebrospinal fluid (CSF) epsilon 3 can also form an SDS-resistant complex with Ass(1-40) but human CSF epsilon;4 cannot. However, when compared with apoE epsilon;3 collected from the conditioned medium of APOE epsilon 3-transfected cells, the competence of equal concentrations of CSF apoE epsilon 3 to form SDS-resistant complexes with Ass(1-40) is apparently diminished. A 1:1 mixture of CSF plus apoE epsilon 3-containing conditioned medium is associated with diminished Ass(1-40) /epsilon;3 complex formation to a greater extent than that observed when an identical volume of phosphate-buffered saline is added to apoE epsilon;3 medium. CONCLUSIONS: These results suggest the presence in CSF of factors that interfere with the formation of complexes between synthetic Ass(1-40) and apoE epsilon 3.

Alzheimer Disease↗
PubMedDate not supplied

Ovariectomy of young mutant amyloid precursor protein transgenic mice leads to increased mortality.

Alzheimer disease (AD) is a neurodegenerative disease affecting a large percentage of the elderly population. Preventative therapies for AD have been limited; however, epidemiological studies have demonstrated that estrogen replacement therapy may prevent or delay the onset of AD. Therefore, we utilized female mutant amyloid precursor protein transgenic mice (APP(SWE)), as a mouse model of AD-like pathology, to study the long-term effects of estrogen withdrawal. Interestingly, by 8 months of age 58% of the ovariectomized APP(SWE) mice had died, whereas there was no mortality in the sham ovariectomized APP(SWE) mice. This mortality was correlated with estrogen loss only in the APP(SEW) mice since background strain matched ovariectomized wild-type mice had virtually no mortality. Cerebral A beta levels in the surviving APP(SWE) ovariectomized females were increased by 50% compared to the sham ovariectomized APP(SWE) females. However, the levels of A beta in the ovariectomized APP(SWE) mice were still well below those observed in 2-year-old APP(SWE) mice that had A beta plaques. Therefore, the mildly increased A beta levels were not the suspected cause of death in these ovariectomized mice. Previous studies have demonstrated increased mortality in mice overexpressing mutant or wildtype APP independent of A beta accumulation; thus, estrogen withdrawal may potentiate this phenotype associated with APP overexpression.

Alzheimer Disease↗