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

E. M. Knight, H. N. Williams, A. C. Stevens, S. H. Kim, J. C. Kottwitz, A. D. Morant, J. W. Steele, W. L. Klein, K. Yanagisawa, R. E. Boyd, D. J. Lockhart, E. R. Sjoberg, M. E. Ehrlich, B. A. Wustman, S. Gandy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Certain mutant Alzheimer's amyloid-β (Aβ) peptides (that is, Dutch mutant APPE693Q) form complexes with gangliosides (GAβ). These mutant Aβ peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing β-hexosaminidase (β-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aβ aggregation and accumulation. The small molecule OT1001 is a β-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for β-hex and low cytotoxicity. Dutch APPE693Q transgenic mice accumulate oligomeric Aβ as they age, as well as Aβ oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APPE693Q mice with OT1001 caused a dose-dependent increase in brain β-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 GAβ accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase β-hex activity may be useful in reducing accumulation of certain mutant species of Aβ and in preventing the associated behavioral pathology.

Original languageEnglish (US)
Pages (from-to)109-117
Number of pages9
JournalMolecular Psychiatry
Issue number1
StatePublished - Feb 5 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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