Viable mouse gene ablations that robustly alter brain Aβ levels are rare.
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.
Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. jeremy.toyn@bms.com
Jeremy H
JH
Toyn
Xu-Alan
XA
Lin
Mark W
MW
Thompson
Valerie
V
Guss
Jere E
JE
Meredith
Sethu
S
Sankaranarayanan
Nestor
N
Barrezueta
John
J
Corradi
Antara
A
Majumdar
Daniel L
DL
Small
Melissa
M
Hansard
Thomas
T
Lanthorn
Ryan S
RS
Westphal
Charles F
CF
Albright
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques / Q000379:methods*; D005820:Genetic Testing / Q000379:methods; D008364:Mannosyltransferases / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010430:Pentosyltransferases / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D008364:Mannosyltransferases; C423034:glycosylphosphatidylinositol mannosyltransferase I; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse