Core AD-Related Biomarkers And Their Associations With T2DM In Aged Cynomolgus Monkeys With Type 2 Diabetes Mellitus

Background:Diabetes mellitus type 2 (T2DM) as one of the most common public health problems [1] It is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.Recently, some studies reported that T2DM is closely associated with the development of AD [2-4] T2DM is an independently risk factor of AD [5].Epidemiological studies have provided direct evidence that T2DM is a strong risk factor for AD and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD as compared with healthy individuals [6]. It has been associated with T2DM at both the molecular and biochemical level from several underlying mechanisms, including metabolic,inflammatory, vascular, and oxidative changes [7-10]. According to recent studies,there are molecular similarities in the inflammatory pathways involved in both AD and T2DM. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood and therefore are worth intensive research.Our review of available evidence from epidemiologic, clinical, and basic research suggests that neural dysfunction from T2DM-related disease results the relationships between T2DM and neural dysfunction are regulated by several modifiers.Objective:We used a series of molecular biology techniques in aged cynomolgus monkeys with spontaneous T2DM to investigate: 1. The relationship between fasting plasma glucose and core AD-related biomarkers such as β-Amyloid 40(Aβ40), P-Amyloid 42 (Aβ42), tau proteins and phosphorylated tau (p-tau) in aged cynomolgus monkeys with spontaneous T2DM. 2. The core AD-related biomarkers levels in CSF and brain tissue are detected and compared between T2DM and normal aged cynomolgus monkeys.Methods:1.Based on FPG test results (FPG > 7.0 mmol/L), plasma levels of T2DM related glycemic parameters (HbA1c、GSP) and lipids (TC、TG、HDL-c、LDL-c)were measured in T2DM and normal aged cynomolgus monkeys, respectively by using blood biochemical analyzer.2.Detecting the plasma levels of T2DM related biomarkers (C-peptide、insulin、glucagon) and core AD-related biomarkers (Aβ42、Aβ40、tau、β-tau) in aged T2DM monkeys and normal controls by using ELISA.3.The CSF core AD-related biomarkers (Aβ42、Aβ40、tau、p-tau181、p-tau 199、p-tau231、p-tau396) were detected in aged T2DM monkeys and normal controls by using ELISA.4.Finally, the immunohistochemical staining technique was used to detect the brain tissue after autopsies.Result:Based on FPG test results, plasma levels of T2DM related glycemic parameters, lipids and core AD-related biomarkers were measured in T2DM(FPG > 7.0 mmol/L) and normal aged cynomolgus monkeys (FPG < 5.6 mmol/L)(age: older than 18-year-old), respectively. The present study revealed significant decreased plasma Aβ42. tau and p-tau levels in aged monkeys with T2DM compared with normal aged controls. The liner regression analysis showed that the fasting plasma glucose (FPG) was negatively associated with fasting plasma Aβ40, p-tau in DM group. The decreased CSF Aβ40 and Aβ42 levels inDM+ group compared with NC+ group significantly. The p-tau immunoreactivity in temporal cortex showed a great number of p-tau labeled neurons in T2DM animals, but not in normal aged animals.Conclusions:Decreased CSF and plasma core AD-related biomarkers’ levels, especially plasma Aβ40 and p-tau levels along with increased FPG in aged T2DM monkeys.There is a being formed AD pathological changes in aged cynomolgus monkeys with spontaneous type 2 diabetes mellitus brain. The study also suggest the improved reliability of the association between T2DM and the core AD-related biomarkers by using non-human primate models and further research is needed.