The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and ne... more The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid /I-peptide (q8) and in recent years, pathogenic mutations in the arnyloid precursor protein (APP) gene have been discovered in some AD families. The APP6701671 mutation, found in a Swedish AD family, has revealed overproduction of &I as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A/l levels in cerebrospinal fluid (CSF) from APPe70,bT1 mutation-carriers and non-carriers. A correlation was seen between ,&PYPOPP in AR l~.,~la m,rl r-h~rstinn nf rlir~nc~ rrlthm,nh nn Iliffa-z=nc-o u,,zc fm,nrl in IP.,P~c nf AR h..aptw~~n thn ~rn,,n~ IlA < L '2-2 nnlml "I.
Evidence is accumulating that neuronal degeneration in the brains of patients with Alzheimer's di... more Evidence is accumulating that neuronal degeneration in the brains of patients with Alzheimer's disease (AD) is accompanied by markers of chronic inflammation. These markers include the activation of microglia and the production of the proinflammatory cytokines TNF-a and IL-1b. Activated microglia release superoxide, which generate reactive oxygen species in the presence of redox-active metals. These, in turn, oxidize lipids to produce 4-hydroxynonenal and other reactive products. Lipid peroxidation adducts as well as other oxidative modifications, including advanced glycation end products and free carbonyls, are observed in the brains of people with AD. In macrophage-lineage cells and in endothelial cells, proinflammatory cytokines induce the expression of an inducible isoform of nitric oxide synthase, which releases relatively high levels of nitric oxide over a long period of time. Nitric oxide and superoxide combine to form peroxynitrite, which damages neurons and other cell types. A marker of peroxynitrite generation is nitrotyrosine, which has been used to demonstrate widespread peroxynitrite-mediated damage in AD brains. If each of the processes described above contributes to the pathogenesis of AD, an effective treatment should: (1) suppress microglial activation; (2) inhibit the production of proinflammatory cytokines; (3) display antioxidant activity; and (4) selectively inhibit the production of NO by the inducible form of NO synthase. The compound should not inhibit constitutive NO synthases in neuronal or endothelial cells, which are required to maintain neuronal function and vascular perfusion.
Background and objective: Alzheimer's disease (AD) is a major health problem in developed countri... more Background and objective: Alzheimer's disease (AD) is a major health problem in developed countries. The absence of specific biomarkers for diagnosis and the multiple limitations of available screening methods have slowed down the efficient implementation of AD population-based screening programs. Based on recent developments, we have designed and tested a new AD vaccine tool kit as an effective framework for large-scale animal model screening. The AD vaccine tool kit was developed for transgenic animal models of AD in order to evaluate their neuropathological characteristics via multiple screening strategies. Methods: This vaccine consists of the inoculation of a new immunogen-adjuvant designed to specifically activate antibodies against the generation of neuritic plaques produced by the toxic excess of amyloid-β (Aß) and simultaneously to deal with the autoimmune activation that triggers acute meningoencephalitis, as observed in human trials in the past. Results: In the present study, we show the current status of the AD vaccine tool kit, with a special focus on the evaluated data and its available settings. We also review the strengths and limitations of this kit in the context of its applicability in experimental research. Conclusions: We focus our attention on the 'framework experimental immunization guidelines' for AD screening, which have recently been boosted by numerous research lines implemented throughout the scientific community.
C-reactive protein (CRP) is an acute phase reactant which humoral concentration rises drastically... more C-reactive protein (CRP) is an acute phase reactant which humoral concentration rises drastically following tissue injury or inflammation. CRP of all species binds to phosphorylcholine residues. In the present studies CRP was found to inhibit platelet-activating factor-induced platelet aggregation, and to stabilize platelet membranes against the lytic effect of lysophosphatidylcholine. Inhibition of platelet aggregation by CRP is accompanied by an inhibition of arachidonic acid release from both phosphatidylcholine and phosphatidylinositol. This suggests that phospholipases are inhibited. Hydrolysis of multilamellar dipalmitoylphosphatidylcholine liposomes by purified phospholipase A2, was also inhibited by CRP. These results suggest that CRP can stabilize membranes from the detergent-like effects of lysolipids and from potentially toxic materials such as platelet-activating factor. By inhibition of phospholipases, production of inflammatory mediators would be blocked. CRP might thu...
1 The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated fro... more 1 The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated from rabbit adipose tissue.
Reduction of the alpha-isoprene unit of polyprenols to form dolichols was studied in vivo using 3... more Reduction of the alpha-isoprene unit of polyprenols to form dolichols was studied in vivo using 3H-polyprenol derivatives as substrates and liposomes as carriers. Liposomes containing labeled polyprenol, polyprenyl phosphate, or polyprenyl pyrophosphate were injected through the portal vein into the livers of rats under anesthesia. Uptake and conversion of the labeled compounds to dolichol derivatives was studied at different intervals. The greatest conversion to dolichol derivatives was found with polyprenyl pyrophosphate and polyprenyl monophosphate, with 31% and 8% of the absorbed dose converted respectively. Less than 0.2% of the absorbed polyprenol was converted to dolichol derivatives. These results suggest that the substrate for the alpha-isoprene reductase involved in dolichol biosynthesis is either polyprenyl monophosphate or polyprenyl pyrophosphate, or both.
Proceedings of the National Academy of Sciences of the United States of America, Jan 6, 1994
The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cereb... more The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism. In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion. Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP). We found a consistent and significant approximately 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation. No significant alterations of other metabolic derivatives of beta APP were dete...
The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and ne... more The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid /I-peptide (q8) and in recent years, pathogenic mutations in the arnyloid precursor protein (APP) gene have been discovered in some AD families. The APP6701671 mutation, found in a Swedish AD family, has revealed overproduction of &I as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A/l levels in cerebrospinal fluid (CSF) from APPe70,bT1 mutation-carriers and non-carriers. A correlation was seen between ,&PYPOPP in AR l~.,~la m,rl r-h~rstinn nf rlir~nc~ rrlthm,nh nn Iliffa-z=nc-o u,,zc fm,nrl in IP.,P~c nf AR h..aptw~~n thn ~rn,,n~ IlA < L '2-2 nnlml "I.
Evidence is accumulating that neuronal degeneration in the brains of patients with Alzheimer's di... more Evidence is accumulating that neuronal degeneration in the brains of patients with Alzheimer's disease (AD) is accompanied by markers of chronic inflammation. These markers include the activation of microglia and the production of the proinflammatory cytokines TNF-a and IL-1b. Activated microglia release superoxide, which generate reactive oxygen species in the presence of redox-active metals. These, in turn, oxidize lipids to produce 4-hydroxynonenal and other reactive products. Lipid peroxidation adducts as well as other oxidative modifications, including advanced glycation end products and free carbonyls, are observed in the brains of people with AD. In macrophage-lineage cells and in endothelial cells, proinflammatory cytokines induce the expression of an inducible isoform of nitric oxide synthase, which releases relatively high levels of nitric oxide over a long period of time. Nitric oxide and superoxide combine to form peroxynitrite, which damages neurons and other cell types. A marker of peroxynitrite generation is nitrotyrosine, which has been used to demonstrate widespread peroxynitrite-mediated damage in AD brains. If each of the processes described above contributes to the pathogenesis of AD, an effective treatment should: (1) suppress microglial activation; (2) inhibit the production of proinflammatory cytokines; (3) display antioxidant activity; and (4) selectively inhibit the production of NO by the inducible form of NO synthase. The compound should not inhibit constitutive NO synthases in neuronal or endothelial cells, which are required to maintain neuronal function and vascular perfusion.
Background and objective: Alzheimer's disease (AD) is a major health problem in developed countri... more Background and objective: Alzheimer's disease (AD) is a major health problem in developed countries. The absence of specific biomarkers for diagnosis and the multiple limitations of available screening methods have slowed down the efficient implementation of AD population-based screening programs. Based on recent developments, we have designed and tested a new AD vaccine tool kit as an effective framework for large-scale animal model screening. The AD vaccine tool kit was developed for transgenic animal models of AD in order to evaluate their neuropathological characteristics via multiple screening strategies. Methods: This vaccine consists of the inoculation of a new immunogen-adjuvant designed to specifically activate antibodies against the generation of neuritic plaques produced by the toxic excess of amyloid-β (Aß) and simultaneously to deal with the autoimmune activation that triggers acute meningoencephalitis, as observed in human trials in the past. Results: In the present study, we show the current status of the AD vaccine tool kit, with a special focus on the evaluated data and its available settings. We also review the strengths and limitations of this kit in the context of its applicability in experimental research. Conclusions: We focus our attention on the 'framework experimental immunization guidelines' for AD screening, which have recently been boosted by numerous research lines implemented throughout the scientific community.
C-reactive protein (CRP) is an acute phase reactant which humoral concentration rises drastically... more C-reactive protein (CRP) is an acute phase reactant which humoral concentration rises drastically following tissue injury or inflammation. CRP of all species binds to phosphorylcholine residues. In the present studies CRP was found to inhibit platelet-activating factor-induced platelet aggregation, and to stabilize platelet membranes against the lytic effect of lysophosphatidylcholine. Inhibition of platelet aggregation by CRP is accompanied by an inhibition of arachidonic acid release from both phosphatidylcholine and phosphatidylinositol. This suggests that phospholipases are inhibited. Hydrolysis of multilamellar dipalmitoylphosphatidylcholine liposomes by purified phospholipase A2, was also inhibited by CRP. These results suggest that CRP can stabilize membranes from the detergent-like effects of lysolipids and from potentially toxic materials such as platelet-activating factor. By inhibition of phospholipases, production of inflammatory mediators would be blocked. CRP might thu...
1 The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated fro... more 1 The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated from rabbit adipose tissue.
Reduction of the alpha-isoprene unit of polyprenols to form dolichols was studied in vivo using 3... more Reduction of the alpha-isoprene unit of polyprenols to form dolichols was studied in vivo using 3H-polyprenol derivatives as substrates and liposomes as carriers. Liposomes containing labeled polyprenol, polyprenyl phosphate, or polyprenyl pyrophosphate were injected through the portal vein into the livers of rats under anesthesia. Uptake and conversion of the labeled compounds to dolichol derivatives was studied at different intervals. The greatest conversion to dolichol derivatives was found with polyprenyl pyrophosphate and polyprenyl monophosphate, with 31% and 8% of the absorbed dose converted respectively. Less than 0.2% of the absorbed polyprenol was converted to dolichol derivatives. These results suggest that the substrate for the alpha-isoprene reductase involved in dolichol biosynthesis is either polyprenyl monophosphate or polyprenyl pyrophosphate, or both.
Proceedings of the National Academy of Sciences of the United States of America, Jan 6, 1994
The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cereb... more The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism. In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion. Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP). We found a consistent and significant approximately 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation. No significant alterations of other metabolic derivatives of beta APP were dete...
Uploads
Papers by Carmen Vigo