title: Evidence that small molecule enhancement of β-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aβ.
abstract: Certain mutant Alzheimer's amyloid-β (Aβ) peptides (that is, Dutch mutant APP(E693Q)) 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 APP(E693Q) 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 APP(E693Q) 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.
authors.affiliation: Departments of Neurology and Psychiatry, and Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Knight
authors.affiliation: Amicus Therapeutics, Cranbury, NJ, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Williams
authors.affiliation: OrPhi Therapeutics, Carlsbad, CA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Stevens
authors.affiliation: Departments of Neurology and Psychiatry, and Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Kottwitz
authors.affiliation: Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Morant
authors.affiliation: OrPhi Therapeutics, Carlsbad, CA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Steele
authors.affiliation: Department of Neurobiology and Cognitive Neurology, and Alzheimer's Disease Center, Northwestern University, Evanston, IL, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Klein
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, Obu City, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yanagisawa
authors.affiliation: Amicus Therapeutics, Cranbury, NJ, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Boyd
authors.affiliation: OrPhi Therapeutics, Carlsbad, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lockhart
authors.affiliation: OrPhi Therapeutics, Carlsbad, CA, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Sjoberg
authors.affiliation: Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Ehrlich
authors.affiliation: OrPhi Therapeutics, Carlsbad, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Wustman
authors.affiliation: 1] Departments of Neurology and Psychiatry, and Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gandy
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001814:Blood-Testis Barrier / Q000187:drug effects; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D013997:Time Factors; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D005732:Gangliosides; D001619:beta-N-Acetylhexosaminidases