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Evidence that small molecule enhancement of ?-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound A?.


ABSTRACT: Certain mutant Alzheimer's amyloid-? (A?) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GA?). These mutant A? peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing ?-hexosaminidase (?-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in A? aggregation and accumulation. The small molecule OT1001 is a ?-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ?-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric A? as they age, as well as A? 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 ?-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? accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase ?-hex activity may be useful in reducing accumulation of certain mutant species of A? and in preventing the associated behavioral pathology.

SUBMITTER: Knight EM 

PROVIDER: S-EPMC5189927 | BioStudies | 2015-01-01T00:00:00Z

REPOSITORIES: biostudies

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