Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila.

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Abeta toxicity. Towards this goal, we generated Abeta transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Abeta and increased lifespan in Abeta flies, whereas loss of function of FKBP52 exacerbated these Abeta phenotypes. Interestingly, the Abeta pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/-) cells have increased intracellular copper and higher levels of Abeta. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Abeta peptides.

Identification of novel genes that modify phenotypes induced by Alzheimer's beta-amyloid overexpression in Drosophila.

Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of beta-amyloid (Abeta) peptides, the complete network of interactions regulating Abeta metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Abeta and we have identified mutations that affect Abeta metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Abeta effects. Several of the mutations that we identified have not been linked to Abeta toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Abeta and open new areas for further study into AD pathogenesis.

[Screening of high efficiency succinonitrile degrading bacterium strains and their degradability].

Succinonitrile used as a sole source of carbon and nitrogen, two bacterium strains, named as J-1-3 and J-13-1, which had high degrading capacity for succinonitrile were isolated and screened out from acrylic fiber wastewater and biofilm in its treatment structure. Through morphological and biochemical method, the two strains were primarily identified as Pseudomonas spp. By tests in shaking flasks, it was determined that the strains can be optimum growth at 30 degrees C, with shaker rotary speed which indirectly reflected aeration capacity at 250 r/min, inoculum amount of 0.1%, and initial pH6. On the optimum conditions for growth, the degradation experiments on different initial concentrations of succinonitrile were carried out. The results indicate that the two strains, especially J-13-1 had high degrading efficiency for succinonitrile. With the initial concentration of succinonitrile at ca. 6000, 8000 and 10,000 mg/L, the degrading rates of succinonitrile by strain J-13-1 reached to 100% after 12.5 h, 14 h and 16 h, respectively.