Dipeptidyl peptidase 4 contributes to Alzheimer's disease-like defects in a mouse model and is increased in sporadic Alzheimer's disease brains.

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid β peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid β peptide, several N-terminally truncated fragments of amyloid β peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid β peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid β, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid β peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid β. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid β peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid β peptide and amyloid β 42-positive plaques and amyloid β 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid β peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression.