Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains

Authors
A Valverde, J Dunys, T Lorivel et al

Lab
Laboratory of Excellence (LABEX) Distalz, INSERM, CNRS, IPMC, Université Côte d'Azur, Valbonne, France

Journal
Journal of Biological Chemistry

Abstract
The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid beta peptides in Alzheimer’s disease, is currently being questioned. In addition to full-length amyloid beta peptide, several N-terminally truncated fragments of amyloid beta peptide could well contribute to Alzheimer’s disease setting and/or progression. Among them, pyroGlu3–amyloid beta 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 beta, but they appear as the rate-limiting enzymes yielding the Glu3–amyloid beta peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3–amyloid beta. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3–amyloid beta peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3–amyloid ptaeptide and amyloid beta 42–positive plaques and amyloid beta 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 beta peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer’s disease progression.

BIOSEB Instruments Used:
Rotarod (BX-ROD),Aron Test or Four Plates Test (LE830)