Scott Webster

Inflammation and Alzheimer’s disease

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimers disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

Inflammation and Alzheimer's disease pathogenesis

Appreciation of the role that inflammatory mediators play in Alzheimers disease (AD) pathogenesis continues to be hampered by two related misconceptions. The first is that to be pathogenically significant a neurodegenerative mechanism must be primary. The second is that inflammation merely occurs to clear the detritis of already existent pathology. The present review addresses these issues by showing that 1) inflammatory molecules and mechanisms are uniquely present or significantly elevated in the AD brain, 2) inflammation may be a necessary component of AD pathogenesis, 3) inflammation may be sufficient to cause AD neurodegeneration, and 4) retrospective and direct clinical trials suggest a therapeutic benefit of conventional antiinflammatory medications in slowing the progress or even delaying the onset of AD.

Aggregation state-dependent Activation of the classical complement pathway by the amyloid β peptide

Abstract: Activation of the classical complement pathway has been widely investigated in recent years as a potential mechanism for the neuronal loss and neuritic dystrophy characteristic of Alzheimers disease (AD) pathogenesis. We have previously shown that amyloid β peptide (Aβ) is a potent activator of complement, and recent evidence suggesting that the assembly state of Aβ is crucial to the progress of the disease prompted efforts to determine whether the ability of Aβ to activate the classical complement pathway is a function of the aggregation state of the peptide. In this report, we show that the fibrillar aggregation state of Aβ, as determined by thioflavin T fluorometry, electron microscopy, and staining with Congo red and thioflavine S, is precisely correlated with the ability of the peptide to induce the formation of activated fragments of the complement proteins C4 and C3. These results suggest that the classical complement pathway provides a mechanism whereby complement‐dependent processes may contribute to neuronal injury in the proximity of fibrillar but not diffuse Aβ deposits in the AD brain.

Relative efficacies of amyloid β peptide (Aβ) binding proteins in Aβ aggregation

The aggregation of amyloid β peptide (Aβ) into its fibrillar, cross β‐pleated configuration is generally viewed as a critical event in the pathophysiology of Alzheimers disease (AD). A diverse group of molecules, the Aβ binding proteins, has been evaluated for their effects on this process. However, most of these studies have used micromolar or greater reagent concentrations, and their different methods have not permitted quantitative comparisons of the efficacy of different Aβ binding proteins in augmenting or inhibiting aggregation. In the present work we have undertaken a coherent analysis using fluorimetry of thioflavin T‐stained experimental solutions. The complement protein C1q, serum amyloid P, and transthyretin significantly enhanced the formation of precipitable, cross β‐pleated aggregates in solutions of 800 nM Aβ1–42. Under these same experimental conditions, α1‐antichymotrypsin had no significant effect on the aggregation process, and both the E3 and E4 isoforms of apolipoprotein E were significant inhibitors. There was a non‐significant trend toward the E3 isoform exhibiting greater inhibition than the E4 isoform. Of the aggregation‐facilitating molecules, C1q was substantially and significantly the most potent.

Epitaxial Nd-doped α-(Al 1−x Ga x ) 2 O 3 films on sapphire for solid-state waveguide lasers

Single-crystal aluminum-gallium oxide films have been grown by molecular beam epitaxy in the corundum phase. Films of the (Al(1-x)Ga(x))(2)O(3) alloys doped with neodymium have favorable properties for solid-state waveguide lasers, including a high-thermal-conductivity sapphire substrate and a dominant emission peak in the 1090-1096 nm wavelength range. The peak position is linearly correlated to the unit cell volume, which is dependent on film composition and stress. Varying the Ga-Al alloy composition during growth will enable the fabrication of graded-index layers for tunable lasing wavelengths and low scattering losses at the interfaces.

Epitaxial neodymium-doped sapphire films, a new active medium for waveguide lasers.

Epitaxial films of neodymium-doped sapphire have been grown by molecular beam epitaxy on R-, A-, and M-plane sapphire substrates. The emission spectrum features sharp lines consistent with single-site doping of the Nd(3+) ion into the host crystal. This material is believed to be a nonequilibrium phase, inaccessible by conventional high-temperature growth methods. Neodymium-doped sapphire has a promising lasing line at 1096 nm with an emission cross section of 11.9x10(-19) cm(2), similar to the 1064 nm line of Nd:YVO(4).

Optical wave propagation in epitaxial Nd:Y2O3 planar waveguides.

Optical wave propagation in neodymium-doped yttrium oxide (Nd:Y(2)O(3)) films grown on R-plane sapphire substrates by molecular beam epitaxy has been studied by the prism coupler method. The measurements yield propagation loss data, the refractive index, and the dispersion relation. The refractive index of the Nd:Y(2)O(3) at 632.8 nm is found to be 1.909, and the lowest propagation loss measured is 0.9 +/- 0.2 cm(-1) at 1046 nm with a polymethyl methacrylate top cladding layer on a film with 6 nm root mean square surface roughness. The loss measurements suggest that the majority loss of this planar waveguide sample is scatter from surface roughness that can be described by the model of Payne and Lacey [Opt. Quantum Electron. 26, 977 (1994)].

Epitaxial Nd:Sapphire Films - Candidate Solid State Laser Material for 1096nm Emission

Nd:Sapphire films grown by molecular beam epitaxy produce sharp emission lines due to identical-site doping not observed in bulk sapphire crystals. The 1096 nm line is a lasing candidate with an Nd:YVO4-like emission cross section.