Abstract
Type 2 diabetes mellitus (T2DM) increases the risk of Alzheimer’s disease (AD)-like dementia and pathology. Endoplasmic reticulum stress (ERS) plays a key role in the development of cognitive impairment in T2DM. Zonisamide (ZNS) was found to suppress ERS-induced neuronal cell damage in the experimental models of Parkinson’s disease (PD). However, the protective effect of Zonisamide in the treatment of diabetes-related dementia is not determined. Here, we studied whether ZNS can attenuate cognitive impairments in T2DM mice. C57BL/6J mice were fed with a high-fat diet (HFD) and received one intraperitoneal injection of streptozotocin (STZ) to develop T2DM. After the 9-week diet, the mice were orally gavaged with ZNS or vehicle for 16 consecutive weeks. We found that ZNS improved spatial learning and memory ability and slightly attenuated hyperglycemia. In addition, the expression levels of synaptic-related proteins, such as postsynaptic density 95 (PSD95) and synaptophysin, were increased along with the activation of the cyclic AMP response element-binding (CREB) protein and cAMP-dependent protein kinase (PKA) both in the hippocampus and cortex of T2DM mice. Meanwhile, ZNS attenuated Aβ deposition, Tau hyperphosphorylation at Ser-396/404, and also decreased the activity of Tau upstream kinases including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Moreover, ZNS also decreased the ERS hallmark protein levels. These data suggest that ZNS can efficiently prevent cognitive impairment and improve AD-like pathologies by attenuating ERS in T2DM mice.
Highlights
Type 2 diabetes mellitus (T2DM) is a peripheral disease exhibiting hyperglycemia induced by insulin resistance
The data showed a significant increase in glucose concentration in T2DM mice at all time points, which depicted an impaired glucose tolerance, while the glucose levels both at 90 and 120 min declined by Zonisamide treatment (Figure 1C)
The higher value of area under the concentration curve (AUC) showed a poor hypoglycemic effect, and we found that the AUC of T2DM mice was significantly increased compared to the control, while Zonisamide treatment slightly affected the area value (Figure 1D)
Summary
Type 2 diabetes mellitus (T2DM) is a peripheral disease exhibiting hyperglycemia induced by insulin resistance. The molecular mechanisms between T2DM and Alzheimer’s disease (AD) are complex (Kandimalla et al, 2017), including insulin resistance, advanced glycation end products (AGE), oxidative stress, inflammation, and mitochondrial dysfunction. All these dysfunctions may contribute to AD-like alteration in T2DM such as impaired synaptic plasticity, the formation of neurofibrillary tangles, and cognitive decline (Bitel et al, 2012; Pugazhenthi et al, 2017). Endoplasmic reticulum stress (ERS) was known to induce cognitive decline in T2DM mice (Zhang et al, 2013; Zhao et al, 2015; Kong et al, 2018). We have evaluated this hypothesis in the HFD-streptozotocin (STZ)-induced T2DM mice
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