REPLYING TO T. Jaworskiet al.Nature480, doi:10.1038/nature10615 (2011)
GSK-3 has been implicated in the pathogenesis of Alzheimer’s disease through regulation of tau phosphorylation, cellular responses to amyloid-β and processing of amyloid precursor protein (APP) to amyloid-β. We previously reported1that inhibition of GSK-3 reduces the accumulation of Aβ40 and Aβ42 (amyloid-ß peptides of 40 and 42 amino acids) in mouse brain and cell culture and that knockdown ofGsk3areduces amyloid-β accumulation in CHO cells, indicating thatGsk3acontributes to the processing of APP in this context1. At about the same time, others reported that knockdown ofGsk3breduces amyloid-β production and overexpression of activeGsk3benhances amyloid-β production2,3,4. A reasonable explanation for these findings, as suggested previously2,5,6, was that both of these highly similar enzymes contribute to APP processing and their respective contributions depend on cell type, relative abundance and assay conditions. Jaworskiet al.7now show that APP can be processed in mouse brain in the absence of eitherGsk3aor neuronalGsk3b.