Introduction: Combination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models.

Methods: We studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model.

Results: We report that an acute 2-week treatment with combined leptin and pioglitazone resulted in a reduction of spatial memory deficits (Y maze) and brain β-amyloid levels (soluble β-amyloid and amyloid plaque burden) relative to vehicle-treated animals. Combination treatment was also associated with amelioration in plaque-associated neuritic pathology and synapse loss, and also a significantly reduced neocortical glial response.

Discussion: Combination therapy with leptin and pioglitazone ameliorates pathologic changes in APP/PS1 mice and may represent a potential treatment approach for AD.