Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

In this study the authors show that Thiamet-G treatment of TAPP mice increases O-GlcNAc levels in the brain and completely prevents cognitive decline. Further, the results found that this blockade in cognitive decline is not likely due to changes in tau hyperphosphorylation or tau aggregation but rather due to alteration in the release or clearance of β-amyloid peptides, which are reflected in the number of amyloid aggregates and plaques. Using a cellular model of APP processing  the authors found that Thiamet-G does not impair release of β-amyloid peptides from APP and thus likely does not directly regulate APP processing, suggesting that O-GlcNAc probably acts at multiple other points in the β-amyloid pathological cascade. Nevertheless, OGA inhibition has positive effects on β-amyloid pathology in TAPP mice that develop synergistic tau and β-amyloid pathologies. In conclusion this study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.