Abstract
BackgroundDiabetes accelerates memory dysfunction in a continuous, slowly pathological process. Studies suggest that the time course of certain biomarkers can characterize the pathological course of the disease to provide information for early intervention. Thus, there is an urgent need for validated biomarkers to characterize the cognitive impairment induced by DM. We aimed to detect changes in cerebrospinal fluid biomarkers such as amyloid β42, phosphorylated tau protein, interleukin 6, and acetylcholine in diabetic rats over time, and to analyse the relationship between diabetes and cognitive impairment.MethodsRats were injected once intraperitoneally with 1% of streptozotocin to establish a diabetic model. Index changes were investigated longitudinally and all were measured at the end of the experiment at day 75. Aβ42, P-tau, IL-6, and ACh levels in CSF, insulin levels in plasma, and Aβ42 levels in plasma and brain tissue were measured by ELISA.ResultsCompared with control, the diabetic model showed ACh in CSF to be decreased by day 15, continuing lower out to day 75. Aβ42 changes in brain and blood showed the same trends but exhibited minima at different time points: day 30 in CSF and day 15 in plasma. After the minimum, Aβ42 in cerebrospinal fluid rose and levelled off lower than in the control group, whereas Aβ42 in plasma rose and went above the controls at day 30, slowly trending upwards for the remainder of the experiment. P-tau protein in CSF in diabetic rats showed an increasing trend, becoming significantly different from the controls at day 60 and day 75. Aβ42 in CSF was strongly negatively correlated with blood glucose at day 15 and was negatively correlated with insulin in serum, particularly at day 45.ConclusionOur longitudinal research model suggest that changes in the measured biomarkers appear before learning and memory impairments do. Aβ42 and ACh in the diabetes model group clearly changed from day 0 to day 45, and then P-tau and IL-6 varied significantly from day 45 to day 75. The reduced ACh levels observed possibly correlated with the factors common to changes in Aβ42, P-tau, and IL-6.
Highlights
Diabetes accelerates memory dysfunction in a continuous, slowly pathological process
Learning and memory ability of rats determined by the eight‐arm maze test After the diabetic rat model had been established for 60 days, learning and memory were tested by the Fasting plasma glucose and insulin levels in diabetic rats Our study found that 43 of 50 rats in experimental diabetic model group had elevated blood glucose levels, defined as higher than 16.7 mmol/L, at 72 h (0 day); control model weight(g)
With synchronous dynamic monitoring of plasma insulin levels in diabetic rats, we found that when the model plasma insulin levels were increased vs. controls, a peripheral insulin resistance phenomenon being dominant, the plasma amyloid β42 (Aβ42) level was significantly increased vs. controls, presumably due to Aβ42 degradation and insulin degradation competing for the same substrate—insulin-degrading enzyme [22, 23]
Summary
Diabetes accelerates memory dysfunction in a continuous, slowly pathological process. Many studies have demonstrated a sequence of changes in neuropsychological and neurological behaviour in patients with diabetes [3, 4], and cognitive impairment with an increased risk of dementia in DM patients has become a serious social problem [5]. The mechanism of vascular dementia involves impairment of the insulin signalling pathway, altered glucose metabolism, metabolic changes such as amyloid β42 (Aβ42) imbalance, phosphorylation of tau protein (P-tau), and release of inflammatory cytokines (e.g. interleukin 6). These changes cause neuronal apoptosis, neuronal damage ( in the hippocampus), structural and functional synaptic damage, and neurotransmitter underexpression, collectively leading to cognitive impairment [6]
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