Alterations in adult hippocampal neurogenesis, aberrant protein s-nitrosylation, and associated spatial memory loss in streptozotocin-induced diabetes mellitus type 2 mice

Abstract

Objective(s): Epidemiological and biochemical studies conducted over the past two decades have established a strong link between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). However, the exact mechanisms through which aberrations in insulin signaling associated with T2DM contribute to cognitive decline are not yet known. Materials and Methods: In an effort to explore possible molecular links between T2DM and AD, the present study investigated the status of neurodegeneration, adult hippocampal neurogenesis, and nitrosative stress induced protein S-nitrosylation in streptozotocin (STZ) induced mice models of T2DM. Morris water maze task and subsequent histological and immunohistochemical assessment were conducted. Expression of neurogenesis markers (Ki67, DCX, and NeuN) and APP 770 was determined by qRT-PCR. Results: A significant decline in spatial learning and reference memory was observed with consequent neurodegeneration in brain cortex and hippocampus in the diabetic group as compared to the control group. A subsequent increase in expression of APP 770 was also observed in T2DM brain regions. Moreover, a significant decrease in transcriptional expression of Ki67, DCX, and NeuN was also evident in T2DM brain regions, which indicated possible aberrations in adult hippocampal neurogenesis in T2DM. Furthermore, an increased immunohistochemical signal for S-nitrosylation was also observed in T2DM, which also suggested its potential contribution in T2DM associated neuronal deterioration. Conclusion: It is suggested that these identified aberrations in the diabetic brain may communally increase the susceptibility of developing AD in patients with T2DM. Further studies of the underlying molecular mechanisms may help to strategize a combination therapy for these debilitating disorders.

Keywords

• Alzheimer’s disease
• Neurodegeneration
• Neurogenesis
• S-nitrosylation
• Type 2 diabetes mellitus