Dean C. Luehrs

Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets

Amyloid-β (Aβ) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimers disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-β peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Aβ peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures. Our experiments revealed that both aorta and platelets contained Aβ peptides, predominately Aβ40. The source of the Aβ pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Aβ42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques. Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Aβ peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls.

Tg-SwDI Transgenic Mice Exhibit Novel Alterations in AβPP Processing, Aβ Degradation, and Resilient Amyloid Angiopathy

Alzheimers disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-beta (Abeta) peptides. We characterized the chemical composition of the Abeta peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse Abeta accumulation. The processing of the N- and C-terminal regions of mutant AbetaPP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S- and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low AbetaPP transgene expression levels, suggests that inefficient Abeta proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic AbetaPP processing and fundamental insights into the faulty degradation and clearance of Abeta in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents.

Dimethyl sulfoxide complexes of silver(I) in solution

Summary The stability constants of dimethyl sulforxide complexes of silver (I) in methanol, 2-butanol, acetone, sulfolane, 70% dioxane, and nitroethane were determined by potentiometric titrations. No dimethyl sulfoxide complexes of silver(I) are formed in water. The stability of dimethyl sulfoxide complexes of silver(I) in a particular solvent depends upon the formal reduction potential of silver(I) in the solvent and the strength of the hydrogen bonding interaction between dimethyl sulfoxide and the solvent.

Infrared and raman spectra of metal 1,2,4,5-benzenetetracarboxylates: Evidence for very short, strong hydrogen bonds

Abstract Salts of 1,2,4,5-benzenetetracarboxylic acid with copper, aluminum, ammonium, cobalt(II), thallium(I), tin(II), uranyl ion, zinc, manganese, iron(II), nickel, potassium and sodium have been prepared and characterized by their IR spectra. The salts of aluminum, ammonium, thallium(I), tin(II), zinc, iron(II), nickel, potassium and sodium had not been reported before with adequate characterization. Raman spectra of selected compounds also aided structural interpretation. The IR spectra of Na 2 C 10 H 4 O 8 ·2H 2 O, Fe(C 10 H 5 O 8 ) 2 ·12H 2 O, Zn(C 10 H 5 O 8 ) 2 ·12H 2 O, Ni(C 10 H 5 O 8 ) 2 ·12H 2 O, (NH 4 ) 3 C 10 H 3 O 8 ·H 2 O and CoC 10 H 4 O 8 ·6H 2 O indicate very short, strong hydrogen bonds in these compounds. The IR and Raman spectra can be used to determine the mode of coordination (if any) of the carboxylate groups of 1,2,4,5- benzenetetracarboxylate to metal ions.

Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer's disease.

Transgenic (Tg) mouse models of Alzheimers disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3 × Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3 × Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3 × Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD.

Crystal structure of cesium 1,2,4,5-benzenetetracarboxylate — a very short hydrogen bond

Abstract The crystal structure of cesium 1,2,4,5-benzenetetracarboxylate has been determined by X-ray diffraction and refined by least-squares methods to R = 0.057 and Rw = 0.067 using 708 reflections. The compound crystallizes in the triclinic space group P 1 with one anion in the unit cell. The lattice parameters are a = 6.8827(6), b = 7.9480(5), c = 5.1033(6) A, α = 92.260(7), β = 104.782(7), γ = 90.970(5)° and V = 269.61 A3. There is a very short hydrogen bond with an O…O distance of 2.42 A. The cesium ion is ten-coordinate with a distorted bicapped square antiprism geometry of oxygens about the cesium.

Polarography of metal ions in hexamethylphosphoramide

Summary The polarographic behavior of oxygen, halide ions and selected metal ions in HMPA was investigated. Solvation of metal ions was found to be stronger than in water but generally similar to that in dimethyl sulfoxide.

Linear free energy relationship of the energy of the CTTS transition of Halide ions with the solvatochromic parameter α

A linear free energy relationship was found betweenvmax, the energy of the absorption maximum of chloride, bromide, or iodide ion in various solvents, and the α solvatochromic parameter which is a measure of the hydrogen bond donor ability of the solvent. The relationships are: for chloride,vmax=6.99α+50.16 kK; for bromide,vmax=5.52α+45.20 kK; for iodide,vmax=5.02α+40.33 kK. The correlation ofvmax for iodide ion with α gave a larger correlation coefficient and smaller standard deviation than a correlation with the ET(30) parameter of Dimroth. From the values ofvmax for iodide ion and the solvated electron in liquid ammonia at 25°C, these correlations indicate a preliminary value of 0.00 for the α parameter of liquid ammonia. This had not been reported before and is lower than expected from a general knowledge of the physical and chemical properties of liquid ammonia but is consistent with a more detailed consideration and recent gas phase measurements of hydrogen bond donor strength.

Hexamethylphosphoramide solvates of alkali metal salts

Abstract The following hexamethylphosphoramide (HMPA) solvates were prepared and characterized by elemental analysis, melting point, and i.r. spectra: LiCl. HMPA, LiBr.4HMPA, LiSCN.HMPA, LiSCN.2HMPA, LiClO4.HMPA, LiClO4.4HMPA, LiNO3.HMPA, LiBF4.HMPA, LiC2H3O2.O. 2HMPA, NaI.HMPA, NaSCN. HMPA, NaSCN. 2HMPA, and NaClO4.HMPA.

Thallium(I) halide complexes in dimethyl sulphoxide

Abstract The solubilities of thallium(I) halides and the stabilities of both cationic and anionic thallium(I) halide complexes in dimethyl sulphoxide were determined. No thallium(I) thiocyanate complexes were found in dimethyl sulphoxide.