The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer’s disease mouse model using magnetic resonance spectroscopy and imaging

• Ibuprofen protects hippocampal volume and NAA loss in triple transgene AD mice.
• Strong correlations are noted between hippocampal volumes and NAA levels.
• APP×PS1×Tau mice, unlike APPxPS1 mice show decreased GABA levels.
• Housing has a strong influence on baseline neurochemical parameters of these mice.
• Tau, but not A-beta levels are protected in APP×PS1×Tau mice with ibuprofen.

We investigated a triple transgene Alzheimer’s disease (AD) mouse model that recapitulates many of the neurochemical, anatomic, pathologic and behavioral defects seen in human AD. We studied the mice as a function of age and brain region and investigated potential therapy with the non-steroidal anti-inflammatory drug ibuprofen. Magnetic resonance spectroscopy (MRS) showed alterations characteristic of AD (i.e. increased myo-inositol and decreased N-acetylaspartate (NAA)). Mice at 6 months of age showed an increase in myo-inositol in the hippocampus at a time when the Aβ is intracellular, but not in amygdala or cortex. Myo-inositol increased as a function of age in the amygdala, cortex and striatum while NAA decreased only in the hippocampus and cortex at 17–23 months of age. Ibuprofen protected the increase of myo-inositol at six months of age in the hippocampus, but had no effect at 17–23 months of age (a time when Aβ is extracellular). In vivo MRI and MRS showed that at 17–23 months of age there was a significant protective effect of ibuprofen on hippocampal volume and NAA loss. Together, these data show the following: the increase in myo-inositol occurs before the decrease in NAA in hippocampus but not cortex; the hippocampus shows earlier changes than does the amygdale or cortex consistent with earlier deposition of Aβ40–42 in the hippocampus and ibuprofen protects against multiple components of the AD pathology. These data also show a profound effect of housing on this particular mouse model.