Xenobiotic compounds modulate cytotoxicity of Aβ amyloids and interact with neuroprotective chaperone L-PGDS

A positive association of the exposure to different classes of xenobiotics such as commonly prescribed drugs and polycyclic aromatic hydrocarbons (PAH) typically those found in air pollution-related particulate matter with Alzheimers disease (AD) may point to direct physical interaction of those compounds with the amyloid formation and clearance processes. In this study, for the first time, we provide evidence of such interactions for three representative compounds from prescription drugs and air pollution, e.g. anticholinergic drugs Chlorpheniramine, a common antihistamine, and Trazodone, an antidepressant as well as 9,10-PQ, a common PAH anthraquinone abundantly present in diesel exhaust and associated with AD. We demonstrate that these three compounds bind to the lipophilic compound carrier and neuroprotective amyloid beta (A{beta}) chaperone lipocalin-type prostaglandin D synthase (L-PGDS) with high affinity attenuating its neuroprotective chaperone function with Chlorpheniramine exhibiting markedly stronger inhibitory effects. We also show that these compounds directly interact with A{beta}(1-40) increasing the fibrils yield with altered fibril morphology and increased the cytotoxicity of the resulting fibrils. We propose that exposure to some xenobiotics in the peripheral tissues such as gut and lungs might result in the accumulation of these compounds in the brain facilitated by the carrier function of L-PGDS. This might lead to attenuation of its neuroprotective function and direct modification of A{beta} amyloid morphology and cytotoxicity. This hypothesis might provide a mechanistic link between exposure to xenobiotic compounds and the increased risk of Alzheimers disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/920884v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@14a4d92org.highwire.dtl.DTLVardef@12aadeeorg.highwire.dtl.DTLVardef@100e5e1org.highwire.dtl.DTLVardef@1f44b9b_HPS_FORMAT_FIGEXP M_FIG C_FIG