Varying degrees of central nervous system neuropathy induced by diabetes mellitus (DM) contribute to a cognitive disorder known as diabetic encephalopathy (DE), which is also one of the independent risk factors for Alzheimer's disease (AD). Endoplasmic reticulum stress (ERS) plays a critical role in the occurrence and development of DE and AD. However, its molecular mechanism remains largely unknown. This study aims to investigate whether thioredoxin-1 (Trx-1) could alleviate DE and AD through ERS, oxidative stress (OS) and apoptosis signaling pathways. Mice were randomly divided into a wild-type group (WT-NC), a streptozotocin (STZ)-treated DM group (WT-DM), a Trx-1-TG group (TG-NC) and a Trx-1-TG DM group (TG-DM). Diabetic animals showed an increase in the time spent in the target quadrant and the number of platform crossings as well as AD-like behavior in the water maze experiment. The immunocontent of the AD-related protein Tau and the levels of cell apoptosis, β-amyloid (Aβ) plaque formation and neuronal degeneration in the hippocampus of the diabetic group were increased. Some key factors associated with ERS, such as protein disulfide isomerase (PDI), glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase-1 (ASK1), c-Jun N-terminal kinase (JNK), protein kinase RNA (PKR)-like ER kinase (PERK), and C/EBP homologous protein (CHOP), were upregulated, and other factors related to anti-oxidant stress, such as nuclear factor erythroid 2-related factor (Nrf2), were downregulated in the DM group. Moreover, DM caused an increase in the immunocontents of caspase-3 and caspase-12. However, these changes were reversed in the Trx-1-tg DM group. Therefore, we conclude that Trx-1 might be a key factor in alleviating DE and AD by regulating ERS and oxidative stress response, thus preventing apoptosis.

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Thioredoxin-1 Is a Target to Attenuate Alzheimer-Like Pathology in Diabetic Encephalopathy by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress.

Diabetic cognitive dysfunction refers to the impairment of cognitive function in diabetic patients, which is a common complication of diabetes. This is especially true for elderly patients with type 2 diabetes mellitus. Studies have shown that adipokines, such as adiponectin (APN) and leptin (LEP) secreted from adipose tissue are implicated not only in the regulation of energy metabolism, but also in the development and progression of diabetic cognitive dysfunction. APN and LEP may serve as biomarkers for diabetes-related cognitive dysfunction. They can cross the blood-brain barrier, enter the brain, and regulate multiple physiological processes such as hippocampal neurogenesis, synaptic plasticity, euroinflammation, oxidative stress, and neuronal apoptosis by binding to the receptors on neurons or glial cells (e.g., microglia and astrocytes), and activating or inhibiting downstream intracellular signaling pathways, including p38MAPK, AMPK, ERK, JAK2/STAT3, PI3K/ AKT, and SIRT1/PGC-1 & alpha;, etc., and subsequently regulate cognitive function. Importantly, APN and LEP may also act as key mediators in the improvement of diabetic cognitive dysfunction by physical exercise. This study aimed to open up ideas for further enriching the theoretical system of "fat-brain" crosstalk, and developing and refining the diagnosis and treatment strategies of diabetic cognitive dysfunction through analyzing the relationship between APN or LEP and diabetic cognitive dysfunction, sorting out the underlying biological mechanism of APN and LEP regulating cognitive function, and exploring the possible mechanism of exercise-mediated APN and LEP in improving diabetic cognitive dysfunction.

The Regulatory Role of Adipokines in Diabetic Cognitive Dysfunction and Br Br

OBJECTIVE To investigate the relevance between spatial learning and memory impairment and the changes of inducible nitric oxide synthase (iNOS) activity, superoxide dismutase (SOD) activity and malondiadehyde (MDA) content in hippocampus from Type 1 diabetic mice.  Methods: Sixty male mice were randomly assigned into a control group (NC group, 20 mice) and a Type 1 diabetic group (DM group, 40 mice). Type 1 diabetic mouse models were established by a large dose intraperitoneal injection of streptozotocin (100 mg/kg). The spatial learning and memory abilities of mice were assessed by Morris water maze (MWM) test. After MWM test, we chose 20 mice (diabetic encephalopathy mice) with the worst spatial learning and memory abilities from diabetic model group, and detected the iNOS activity, SOD activity and MDA content in hippocampus in both groups.  Results: Compared with the NC group, the escape latency was significantly extended and platform crossings were significantly declined in diabetic mice (P<0.01). Furthermore, the activity of iNOS and the content of MDA were markedly increased, and the activity of SOD was significantly decreased in hippocampus of diabetic encephalopathy mice (P<0.01).  Conclusion: The established Type 1 diabetic mice show symptoms of cognitive dysfunction, which might be related to the increase of oxidative stress in hippocampus.

Impairment of spatial learning and memory and changes of oxidative stress in hippocampus from Type 1 diabetic mice

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Impairment of spatial learning and memory and changes of oxidative stress in hippocampus from Type 1 diabetic mice