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

Jeremy H Toyn,Xu-Alan Lin,Daniel L Small,Nestor Barrezueta,Charles F Albright,Valerie Guss,Ryan S Westphal,Thomas Lanthorn,Melissa Hansard,Mark W Thompson,Antara Majumdar,John Corradi,Jere E Meredith,Sethu Sankaranarayanan

doi:10.1186/1471-2202-11-143

Jeremy H Toyn, Xu-Alan Lin + Show 12 more

Open Access

https://doi.org/10.1186/1471-2202-11-143

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Abstract

BackgroundAccumulation 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.ResultsTo 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).ConclusionsThus, gene ablations that are permissive for mouse survival and that also have a robust effect on Aβ levels in the brain are rare.

Highlights

Accumulation of amyloid-b (Ab) peptide in the brain is thought to play a key pathological role in Alzheimer’s disease
Ab is a secreted peptide formed through consecutive proteolytic cleavages of the amyloid precursor protein (APP) by the b-site APP cleaving enzyme (BACE1), which releases the N-terminal end of Ab, and g-secretase, which releases a range of Ab C-terminal ends resulting in Ab peptides of typically 37-42 amino acids in length
A screen of mouse KO strains for altered brain Ab levels Mouse knock-out (KO) strains were generated over a period of four years, and brain samples were collected and assayed during this time on an ongoing basis

Summary

Introduction

Accumulation of amyloid-b (Ab) peptide in the brain is thought to play a key pathological role in Alzheimer’s disease. APP-mediated changes in Ab can result from increased cleavage of the nonamyloidogenic a-site of APP, competing with BACE1 for the available APP substrate, as reviewed by Fahrenholz [37]. Metalloproteases such as ADAM10 [38] carry out a-site cleavage, which can be activated via multiple targets, including retinoic acid receptor [39,40] liverX-receptor, muscarinic acytylcholine receptor M1 [41,42], G protein coupled receptor PAC1 [43], protein kinase C [44,45], and low cholesterol [46]

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