Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice

We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-p within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage.. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of beta APP and A beta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD. (C) 2009 Elsevier Inc. All rights reserved.