Combination therapy in a transgenic model of Alzheimer's disease.

ABSTRACT

The pathological accumulation of the ß-amyloid protein (Aß) has been closely associated with synaptic loss and neurotoxicity contributing to cognitive dysfunction in Alzheimer's disease (AD). Oligomers of Aß42 appear to be the most neurotoxic form. Two of the most promising attempts to reduce Aß accumulation have been with scyllo-inositol, an inositol steroisomer, that stabilizes Aß42 peptide and prevents it from progressing to oligomers and fibrils and R-flurbiprofen, a purified enantiomer of the classical racemic non-steroidal anti-inflammatory drugs (NSAID), flurbiprofen, that retains the ability to specifically lower Aß42. In the present study we evaluated the effects of scyllo-inositol and the combination treatment of scyllo-inositol+R-flurbiprofen on amyloid pathology and hippocampal-dependent memory function in 5XFAD mice, a model of Aß pathology characterized by an enormous production of Aß42. Our expectations were that the combination treatment of scyllo-inositol+R-flurbiprofen would have an additive effect in preventing Aß accumulation and that cognition would be improved. Mice treated with scyllo-inositol exhibit 41 and 35% reduction in the deposition of the amyloid plaques stained by antibody against Aß42 and Aß40 respectively. Scyllo-inositol was not more effective when combined with R-flurbiprofen for the measures tested. Scyllo-inositol treated mice performed significantly better at the radial arm water maze (RAWM) task than untreated and scyllo-inositol+R-flurbiprofen treated mice.