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Abstract
Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT).Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer’s Association workgroups criteria.Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile (P < 0.001). The odds ratios (ORs) for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001). In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36–3.76) than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a (P < 0.05), but not with higher IL-6, CRP or lower GLP-1.Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.
Highlights
MATERIALS AND METHODSMild cognitive impairment is accepted as an intermediate stage between normal cognitive functioning and dementia (Petersen, 2004; Petersen et al, 2009)
Patients with higher Dipeptidyl peptidase-4 (DPP4) activities tended to be relatively old (P = 0.006) with high levels of BMI, TG, IL-6, C-reactive protein (CRP), nitrotyrosine, and 8-iso-PGF2a, and lower fasting active glucagon-like peptide-1 (GLP-1) and Montreal Cognitive Assessment (MoCA) score (P < 0.001); Table 2 showed that participants with impaired cognitive function had higher nitrotyrosine, 8-iso-PGF2a, DPP4 activity, and lower MoCA score compared to those without impaired cognitive function
Correlation analysis showed that plasma DPP4 activities were positively and significantly related to age (r = 0.074, P = 0.009), BMI (r = 0.130, P < 0.001), IL-6 (r = 0.305, P < 0.001), CRP (r = 0.243, P < 0.001), nitrotyrosine (r = 0.294, P < 0.001), 8-iso-PGF2a (r = 0.333, P < 0.001) and negatively with fasting active GLP-1 (r = −0.146, P < 0.001) and MoCA score (r = −0.299, P < 0.001)
Summary
MATERIALS AND METHODSMild cognitive impairment is accepted as an intermediate stage between normal cognitive functioning and dementia (Petersen, 2004; Petersen et al, 2009). Once mild cognitive impairment becomes more advanced, interventions targeted at pathogenesis of dementia are unlikely to delay further cognitive impairment (Kaduszkiewicz et al, 2005; Salloway et al, 2009; Sperling et al, 2011; Zheng et al, 2016). Dipeptidyl peptidase-4 (DPP4) is a widely expressed multifunctional exopeptidase that exists as a membraneanchored cell surface protein or in a soluble form in the plasma (Matteucci and Giampietro, 2009). It has been identified as a novel adipokine playing crucial roles in GLP-1 degradation and in the development of inflammation and oxidative stress (Drucker and Nauck, 2006; Lamers et al, 2011; Zheng et al, 2015a,b). Animal studies have proved that DPP4 activity inhibitors ameliorated cognitive impairment through suppressing inflammatory reaction, oxidative stress, or GLP-1 degradation (Gault et al, 2015; Ma et al, 2015; Tsai et al, 2015)
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