Background: Accumulation of amyloid-b (Ab) peptide in the brain is thought to play a key pathological role in Alzheimer’s disease. Many pharmacological targets have therefore been proposed based upon the biochemistry of Ab, but not all are equally tractable for drug discovery. Results: To search for novel targets that affect brain Ab without causing toxicity, we screened mouse brain samples from 1930 novel gene knock-out (KO) strains, representing 1926 genes, using Ab ELISA assays. Although robust Ab lowering was readily apparent in brains from a BACE1 KO strain, none of the novel strains exhibited robust decreases in brain Ab, including a GPR3 KO strain, which had previously been proposed as an Ab target. However, significantly increased Ab was observed in brain samples from two KO strains, corresponding to genes encoding the glycosylphosphatidylinositol mannosyl transferase PIGZ and quinolinate phosphoribosyltransferase (QPRT). Conclusions: Thus, gene ablations that are permissive for mouse survival and that also have a robust effect on Ab levels in the brain are rare. Background The amyloid hypothesis states that Alzheimer ’ diseas
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