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

Abstract

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.

Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes

“…We previously reported deficits on hippocampus-dependent memory in the Morris water maze task and FC in the Dutch APP mouse line. 12 , 23 Here, we chose a battery of tasks that target both hippocampus-dependent memory as well as the entorhinal cortex and amygdala to assess complete memory function; these include FC, 17 , 23 NOR, 17 , 23 and Y-maze SA (previously untested), or anxiety-like behaviors using the EPM (previously reported 17 , 23 ). Three-month treatment of Dutch APP mice by once-weekly subcutaneous injection of neat IG prevented onset of NOR ( figure 4A ), SA ( figure 4B ), and FC ( figure 4C ) deficits, without affecting anxiety-like behavior in the EPM ( figure 4D ) in female Dutch APP mice.…”

“…Memory was assessed in the novel object recognition (NOR), Y-maze spontaneous alternation (SA), and contextual/cued FC tests and anxiety-like behavior assessed in the elevated plus maze (EPM) as previously described. 17 , 18 …”

Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention

“…A more recent study confirming the effect of GD3S-deficient mice also suggests an impact of the cholinergic-specific ganglioside, GT1a, in memory retention (167). An increase of -hexosaminidase, which is a catabolic enzyme in ganglioside homeostasis, revealed beneficial effects in cognitive tests with transgenic AD mouse models (168). The importance of this catabolic enzyme is also underlined by a study showing changed hexosaminidase and -galactosidase in AD patients (169), probably linked with a dysfunction of lysosomal compartments, a known characteristic in AD (170,171).…”

Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1

“…Short-term non-associative memory based on the natural exploration of novelty in mice was assessed in the novel object recognition test as described [ 26 ]. Briefly, on day 1, the mouse was habituated in the NOR arena (20 cm diameter) for 10 min.…”