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Open Access Highly Accessed Research article

Viable mouse gene ablations that robustly alter brain Aβ levels are rare

Jeremy H Toyn1*, Xu-Alan Lin1, Mark W Thompson1, Valerie Guss1, Jere E Meredith1, Sethu Sankaranarayanan1, Nestor Barrezueta2, John Corradi2, Antara Majumdar3, Daniel L Small45, Melissa Hansard4, Thomas Lanthorn4, Ryan S Westphal1 and Charles F Albright1

Author Affiliations

1 Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA

2 Applied Genomics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA

3 Global Biometric Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA

4 Lexicon Pharmaceuticals, Department of Neurology, 8800 Technology Forest Place, The Woodlands, Texas 77381, USA

5 MDS Pharma Services, 22011 30th Dr SE, Bothell, WA 98021, USA

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BMC Neuroscience 2010, 11:143  doi:10.1186/1471-2202-11-143

Published: 5 November 2010

Abstract

Background

Accumulation of amyloid-β (Aβ) 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 Aβ, but not all are equally tractable for drug discovery.

Results

To search for novel targets that affect brain Aβ without causing toxicity, we screened mouse brain samples from 1930 novel gene knock-out (KO) strains, representing 1926 genes, using Aβ ELISA assays. Although robust Aβ lowering was readily apparent in brains from a BACE1 KO strain, none of the novel strains exhibited robust decreases in brain Aβ, including a GPR3 KO strain, which had previously been proposed as an Aβ target. However, significantly increased Aβ 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 Aβ levels in the brain are rare.