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Cognitive dysfunction is one of the complications of diabetes. Unfortunately, there is no effective methods to block its progression currently. One of the pathophysiological mechanisms is synaptic protein damage and neuronal signal disruption because of glucose metabolism disorder. Dystroglycan protein, located in the post‐synaptic membrane of neurons, links the intracellular cytoskeleton with extracellular matrix. Abnormal expression of dystroglycan protein affects neuronal biological functions and leads to cognitive impairment. However, there are no relevant studies to observe the changes of β‐dystroglycan protein in diabetes rat brain and in primary neurons under high glucose exposure. Our data demonstrated the alterations of cognitive abilities in the diabetic rats; β‐dystroglycan protein degradation occurred in hippocampal and cortical tissues in diabetic rat brain. We further explored the mechanisms underlying of this phenomenon. When neurons are exposed to high glucose environment in long‐term period, microRNA‐132 (miR‐132) would be down‐regulated in neurons. Matrix Metalloproteinases‐9 (MMP‐9) mRNA, as a target of miR‐132, could be up‐regulated; higher expression and overlay activity of MMP‐9 protein could increase β‐DG protein degradation. In this way, β‐DG degradation may affect structure and functions among the synapses, which related to cognition decline. It may provide some theoretical basis for elucidating the molecular mechanism of diabetes‐induced cognitive dysfunction.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cerebral ischemia injury via regulating the level of asymmetric dimethylarginine (ADMA). This study is aimed at exploring the effect of adiponectin resistance on ADMA-induced neuronal loss in ischemic stroke (IS) and the underlying mechanism. DDAH1 knockout (DDAH1-/-) and wild-type (DDAH1+/+) rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R). Plasma and brain adiponectin levels and the expressions of adiponectin receptor 1 (APR1), adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK were determined after 24 h, 3 days, and 7 days. Neurological behavior, infarct volume, and adiponectin signaling were evaluated using adiponectin peptide or AdipoRon. The levels of reactive oxygen species (ROS) and Forkhead box O1 (FOXO1) (a transcription factor for APR1) were also assessed. An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in primary neurons. DDAH1 was overexpressed in neurons, after which FOXO1 expression, ROS production, adiponectin resistance, and cell viability were detected. DDAH1-/- rats showed no significant difference in adiponectin level in either plasma or brain after MCAO/R in DDAH1+/+ rats, but downregulated APR1 expression and suppressed adiponectin signaling were observed. AdipoRon, but not adiponectin peptide, attenuated the neurological deficits and adiponectin resistance in DDAH1-/- rats. ROS accumulation and phosphorylated FOXO1 expression also increased with DDAH1 depletion. Following DDAH1 overexpression, decreased cell viability and inhibited adiponectin signaling induced by OGD/R were alleviated in primary neurons, accompanied by reduced ROS production and phosphorylated FOXO1 expression. Our study elucidated that in IS, DDAH1 protected against adiponectin resistance in IS via the ROS/FOXO1/APR1 pathway.

A part of the axonal cytoskeleton protein complex, neurofilament light chain (NF-L) has been suggested as a pathological hallmark in various neurological disorders, including hemorrhagic stroke, vascular dementia, and cerebral small vessel disease. Neuroaxonal debris are mainly engulfed and phagocytosed by microglia, while the effects of NF-L on microglia have not been elucidated. Ferritin heavy chain (FTH) not only reflects the age-related status of microglia but may also be secreted into the extracellular space. After treatment of microglia with varying concentrations of NF-L (0-3 μg/ml), we found robust increases in the number of secretory FTH-containing exosomes in the medium. Induction of the FTH-containing exosomes secreted from microglia stimulates neuronal loss and membrane lipid peroxidation, as assessed by CKK8 and C11-Bodipy581/591, respectively. However, this oxidative stress damage was attenuated by blocking Fth1 expression. Our results suggest that NF-L, as a biomarker of axonal injury itself, could participate in neuronal ferroptosis in a nonclassical manner by secreting FTH-containing exosomes from microglia into the extracellular matrix.

Background: Osteocalcin is related to energy metabolism, memory and the acute stress response, suggesting a relationship between bone and the brain. The need to explore the effect of osteocalcin on acute ischemic stroke is therefore urgent. Results: Patients with better outcomes had higher serum osteocalcin levels than those whose NIHSS scores did not improve. Multivariable logistic regression analysis showed acceptable performance (area under the curve = 0.766). The effect of osteocalcin on the promotion of neuron survival was confirmed by Cell Counting Kit-8 experiments. In addition, osteocalcin could decrease proline hydroxylase 1 and inhibit the degradation of gasdermin D. Conclusions: We propose that osteocalcin can improve outcome after acute ischemic stroke in the acute period. By downregulating proline hydroxylase 1, osteocalcin leads glucose metabolism to the pentose phosphate pathway and therefore promotes neuronal survival through inhibiting pyroptosis. Methods: Demographic data and laboratory results were obtained from patients with ischemic stroke in the acute period for analysis. A receiver operating characteristic curve was used to assess the discrimination of the prediction model. The potential effect of osteocalcin on cerebral ischemia and osteocalcin mechanism were explored in cultured primary rat cerebral cortical neurons treated with oxygen-glucose deprivation and reoxygenation.

The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01070-5.

Compelling evidence from basic molecular biology has demonstrated the crucial role of microglia in the pathogenesis of Alzheimer's disease (AD). Microglia were believed to play a dual role in both promoting and inhibiting Alzheimer's disease progression. It is of great significance to regulate the function of microglia and make them develop in a favorable way. In the present study, we investigated the function of repressor element 1-silencing transcription factor (REST) in Aβ1-42-induced BV-2 cell dysfunction. We concluded that Aβ1-42 could promote type I activation of BV-2 cells and induce cell proliferation, migration, and proinflammation cytokine TNF-α, IL-1β, and IL-6 expression. Meanwhile, REST was upregulated, and nuclear translocalization took place due to Aβ1-42 stimulation. When REST was knocked down by a specific short hairpin RNA (sh-RNA), BV-2 cell proliferation, migration, and proinflammation cytokine expression and secretion induced by Aβ1-42 were increased, demonstrating that REST may act as a repressor of microglia-like BV-2 cell activation.

Background: Bone is recently confirmed to be an endocrine organ, and may influence the neuron, leading to the cognitive decline and emotional disorder. However, the interaction between bone and cerebral white matter hyperintensities (WMH) is still unclarified in type 2 diabetes patients. Methods: WMH was quantified on magnetic resonance imaging (MRI) using the Fazekas and Schmidt's scoring protocol. Patients with scores ranging from 0 to 1 were defined as none or mild WMH (Group 1), and patients with scores ranging from 2 to 3 as severe WMH (Group 2). Logistic regression analysis was done to determine the association between WMH severity and selected clinical factors. Findings: Of the 194 subjects who were included in the study, there were significant differences among the two groups with respect to age and osteocalcin. After adjustment for possible confounders, age (odds ratio (OR): 1.07; 95% confidence interval (CI): 1.04-1.12; P < 0.001) and low density lipoprotein (OR: 1.51; 95% CI: 1.09-2.08; P =0.012) were associated with severe WMH, while osteocalcin could decrease the severity of WMH (OR: 0.96; 95% CI: 0.84-0.98; P =0.014). Interpretation: Our data indicate that aging, lower osteocalcin and higher LDL are associated with severe WMH in type 2 diabetes patients. The mechanism of the relationship between osteocalcin and WMH needs further research. Funding Statement: This work was supported by General Scientific Research Project of Zhejiang Education Department (Y201838964), Project of medicine and health technology program in Zhejiang province (2019314900). Declaration of Interests: All authors declare that they have no conflict of interest. Ethics Approval Statement: Ethics approval was obtained from the Ethics Board of Shanghai Tenth People’s Hospital.