AADvac1, an Active Immunotherapy for Alzheimer's Disease and Non Alzheimer Tauopathies: An Overview of Preclinical and Clinical Development.

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer's disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer's. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients' brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer's disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

High-performance liquid chromatographic determination of azaarenes and their metabolites in groundwater affected by creosote wood preservatives.

Polynuclear azaheterocyclic compounds (azaarenes) are nitrogen-containing analogs of polycyclic aromatic hydrocarbons (PAHs). The nitrogen atom in the ring system causes these compounds to be slightly polar and considerably more water soluble than related PAHs. A method using a solid-surface sorption technique to extract and concentrate azaarenes and their principle metabolites present in groundwater that contains creosote waste is described. Analyte isolation and concentration is accomplished by solid-phase extraction on n-octadecyl cartridges followed by instrumental determination involving high-performance liquid chromatography. Separations and detection are achieved using flexible-walled, wide-bore columns with ultraviolet and fluorescence photometric detectors connected in series. Fluorescence detection alone is insufficient because the fluorescence response produced by two-ring azaarenes is limited. Short wavelength (229 nm) absorbance detection provides improved sensitivity for these compounds and peak rationing for more definitive identification. In this study, oxygen-containing metabolites of quinoline, isoquinoline, and acridine are detected in groundwater from hazardous waste sites in Pensacola, Florida and St. Louis Park, Minnesota. Concentrations ranging from mg/L to ng/L are measured. The dependence of measured octanol-water partition coefficients on pH is discussed in the context of the isolation chemistry. As a direct bacterial degradation product of acridine with a relatively long environmental persistence, 9-acridinone may serve as a biogenic marker signaling creosote contamination of groundwater.