Prolyl endopeptidase and dipeptidyl peptidase IV are associated with externalizing and aggressive behaviors in normal and autistic adolescents.

Aims: Peptides and a dysregulated immune system play a role in the pathophysiology of autism. Dysfunctions in prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP-IV) may underpin both the peptidergic and immune alterations in autism. The aims of this study are to: (i) delineate serum PEP and DPP-IV enzyme activities in autism, and (ii) examine the associations between both peptidases and behavioral characteristics or immune variables.

Main Methods: We included 18 autistic patients and 22 healthy controls and measured the Child Behavior Checklist (CBCL), serum PEP and DPP-IV and immune biomarkers, i.e. the serum protein fractions α1, α2 and γ, and immunoglobulins, i.e. IgG1, IgG2, IgG3 and IgG4. Results were adjusted for possible effects of age and body mass index (BMI).

Key Findings: There were no significant differences in PEP or DPP-IV between the autistic patients and controls. DPP-IV was significantly and positively associated with the CBCL attention problems, aggressive and externalizing behavior subscales. PEP was significantly and positively associated with the CBCL delinquent, aggressive, externalizing and internalizing behavior subscales. There was a negative correlation between both peptidases and age and Tanner stage. DPP-IV was associated with α2-globulin (positively) and IgG3 (inversely) levels, while PEP activity was correlated with IgG2 levels (inversely). BMI was significantly associated with aggressive and externalizing behaviors.

Significance: These findings demonstrate an association between peptidases and aggressive and externalizing behaviors, which may be explained by effects of these peptidases cleaving behavioral neuropeptides. Both peptidases are associated with immune biomarkers suggesting multiple bidirectional effects.