Evidence that small molecule enhancement of β-hexosaminidase activity corrects the behavioral phenotype in Dutch APPE693Q mice through reduction of ganglioside-bound Aβ

Certain mutant Alzheimer's amyloid-beta (A beta) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GA beta). These mutant A beta peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing beta-hexosaminidase (beta-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in A beta aggregation and accumulation. The small molecule OT1001 is a beta-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for beta-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric A beta as they age, as well as A beta oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain beta-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GA beta accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase beta-hex activity may be useful in reducing accumulation of certain mutant species of A beta and in preventing the associated behavioral pathology.