Diabetes-induced Cognitive Decline Research Articles

Guardians of Neurons: The Cntf Gene and Ciliary Neurotrophic Factor (CNTF) in the Genetic Landscape of Alzheimer’s Disease Neuroprotection

Background: Type II Diabetes Mellitus (Type II DM) is a complex systemic disorder that affects various organs and has been strongly associated with an increased risk of cognitive impairments, including dementia. The Ciliary Neurotrophic Factor (CNTF) gene is implicated in the pathophysiology of diabetes-induced cognitive decline, suggesting its potential as a biomarker for neurodegenerative diseases. Objective: The primary objective of this study was to investigate the expression of the CNTF gene in diabetic patients with dementia and to evaluate its correlation with cognitive dysfunction. Methods: A cohort of 88 diabetic dementia patients and 12 healthy controls was selected based on inclusion criteria. CNTF serum levels were measured using Chemiluminescent immunoassay (CLIA), and CNTF gene expression was assessed through real-time PCR. DNA was isolated using the QIAgen blood kit, followed by bisulfite DNA modification and Methylation Specific PCR for methylation profiling. Data analysis included comparative studies using GraphPad Prism 9.0 with statistical significance set at a p-value of <0.05. Results: The study found that CNTF serum levels in diabetic dementia patients (n=88) were significantly lower at 4.98 µg/mL compared to 14.21 µg/mL in healthy controls (n=12). MMSE scores were also reduced in the patient cohort, averaging 10.98 versus 25.6 in controls. A notable decrease in CNTF gene expression was observed with a fold change of approximately 4.1 in diabetic dementia patients, indicating underexpression in this group. Conclusion: CNTF gene expression is inversely correlated with cognitive function in diabetic patients, suggesting that CNTF could serve as a useful biomarker for the early detection of dementia in this population. The identification of this gene's role opens new avenues for targeted therapeutic interventions and enhances the understanding of dementia's etiology in diabetic patients.

Fibroblast growth factor 21 alleviates diabetes-induced cognitive decline.

Diabetes mellitus (DM) causes damage to the central nervous system, resulting in cognitive impairment. Fibroblast growth factor 21 (FGF21) exhibits the potential to alleviate neurodegeneration. However, the therapeutic effect of intracerebroventricular (i.c.v) FGF21 infusion on diabetes-induced cognitive decline (DICD) and its potential mechanisms remain unclear. In this study, the impact of FGF21 on DICD was explored, and 1H nuclear magnetic resonance (NMR)-based metabolomics plus 13C NMR spectroscopy in combine with intravenous [1-13C]-glucose infusion were used to investigate the underlying metabolic mechanism. Results revealed that i.c.v FGF21 infusion effectively improved learning and memory performance of DICD mice; neuron loss and apoptosis in hippocampus and cortex were significantly blocked, suggesting a potential neuroprotective role of FGF21 in DICD. Metabolomics results revealed that FGF21 modulated DICD metabolic alterations related to glucose and neurotransmitter metabolism, which are characterized by distinct recovered enrichment of [3-13C]-lactate, [3-13C]-aspartate, [4-13C]-glutamine, [3-13C]-glutamine, [4-13C]-glutamate, and [4-13C]- γ-aminobutyric acid (GABA) from [1-13C]-glucose. Moreover, diabetes-induced neuron injury and metabolic dysfunctions might be mediated by PI3K/AKT/GSK-3β signaling pathway inactivation in the hippocampus and cortex, which were activated by i.c.v injection of FGF21. These findings indicate that i.c.v FGF21 infusion exerts its neuroprotective effect on DICD by remodeling cerebral glucose and neurotransmitter metabolism by activating the PI3K/AKT/GSK-3β signaling pathway.

The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats.

Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown. Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment. When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213. In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.

Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.

Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.

The Reciprocal Causation of the ASK1-JNK1/2 Pathway and Endoplasmic Reticulum Stress in Diabetes-Induced Cognitive Decline.

Diabetes significantly induces cognitive dysfunction. Neuronal apoptosis is the main cause of diabetes-induced cognitive decline (DICD). Apoptosis signal-regulating kinase 1 (ASK1) and endoplasmic reticulum (ER) stress are remarkably activated by diabetes. The role and relationship of ASK1-JNK1/2 signaling and ER stress in DICD have not yet been elucidated. In this study, we used db/db mice as the DICD animal model and confirmed that db/db mice displayed cognitive decline with inferior learning and memory function. Diabetes significantly induced morphological and structural changes, excessive neuronal apoptosis, Aβ1–42 large deposition, and synaptic dysfunction in the hippocampus. Mechanistic studies found that diabetes significantly triggered ASK1-JNK1/2 signaling activation and increased ER stress in the hippocampus. Moreover, diabetes enhanced the formation of the IRE1α–TRAF2–ASK1 complex, which promotes the crosstalk of ER stress and the ASK1-JNK1/2 pathway during DICD. Furthermore, 4-PBA treatment blocked high glucose (HG)-induced ASK1-JNK1/2 signaling activation, and excessive apoptosis in vitro. Inhibiting ASK1 via siRNA remarkably ameliorated the HG-induced increase in p-IRE1α and associated apoptosis in SH-SY5Y cells, suggesting that ASK1 is essential for the assembly and function of the proapoptotic kinase activity of the IRE1α signalosome. In summary, ER stress and ASK1-JNK1/2 signaling play causal roles in DICD development, which has crosstalk through the formation of the IRE1α–TRAF2–ASK1 complex.

NMR-based metabolomics characterizes metabolic changes in different brain regions of streptozotocin-induced diabetic mice with cognitive decline.

Diabetes at advanced age increases rise of cognitive impairment, but its potential mechanisms are still far from being fully understood. In this study, we analyzed the metabolic alterations in six different brain regions between streptozotocin (STZ)-induced diabetic mice with cognitive decline (DM) and age-matched controls (CON) using a 1H NMR-based metabolomics approach, to explore potential metabolic mechanisms underlying diabetes-induced cognitive decline. The results show that DM mice had a peculiar metabolic phenotype in all brain regions, mainly involving increased lactate level, decreased choline and energy metabolism as well as disrupted astrocyte-neuron metabolism. Furthermore, these metabolic changes exhibited a brain region-specific pattern. Collectively, our results suggest that brain region-specific metabolic disorders may be responsible for diabetes-induced cognitive dysfunction.

Exogenous fibroblast growth factor 1 ameliorates diabetes-induced cognitive decline via coordinately regulating PI3K/AKT signaling and PERK signaling

BackgroundDiabetes induces central nervous system damage, leading to cognitive decline. Fibroblast growth factor 1 (FGF1) has dual function of neuroprotection and normalizing hyperglycemia. To date, the precise mechanisms and potential treating strategies of FGF1 for diabetes-induced cognitive decline (DICD) hasn’t been fully elucidated.MethodsIn this study, db/db mice were used as DICD animal model. We found that diabetes remarkably suppressed FGF1 expression in hippocampus. Thus, exogenous FGF1 had been treated for db/db mice and SH-SY5Y cells.ResultsFGF1 significantly ameliorates DICD with better spatial learning and memory function. Moreover, FGF1 blocked diabetes-induced morphological structure change, neuronal apoptosis and Aβ1–42 deposition and synaptic dysfunction in hippocampus. But normalizing glucose may not the only contributed factor for FGF1 treating DICD with evidencing that metformin-treated db/db mice has a inferior cognitive function than that in FGF1 group. Current mechanistic study had found that diabetes inhibits cAMP-response element binding protein (CREB) activity and subsequently suppresses brain derived neurotrophic factor (BDNF) level via coordinately regulating PERK signaling and PI3K/AKT signaling in hippocampus, which were reversed by FGF1.ConclusionWe conclude that FGF1 exerts its neuroprotective role and normalizing hyperglycemia effect, consequently ameliorates DICD, implying FGF1 holds a great promise to develop a new treatment for DICD.61Q3XReLNTPu_dAr92-AxWVideo abstract

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study.

Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

Intermittent Fasting Alleviates Diabetes-induced Cognitive Decline via Gut Microbiota-metabolites-brain Axis (OR32-04-19)

ObjectivesCognitive decline is one of severe type 2 diabetes complications. Intermittent fasting (IF) is a promising dietary intervention for T2D risk reduction, but its protective effect and mechanism on diabetic cognitive dysfunction remain elusive. Gut microbiota plays a vital role interphasing diet and host physiology and pathology and highly affected by the dietary composition and patterns. It has been reported that the microbiota homeostasis is essential for maintenance of gut health and for modulating cognitive function. We hypothesized that gut microbiota might play a pivotal role in mediating protective effects of IF on diabetes-induced cognitive decline. MethodsAfter a 28-day IF regimen treatment, cognitive behavioral tests and brain insulin signaling were assessed on db/db mice. The microbiota-metabolites-brain axis alterations were detected by multiple-omics analysis (transciptomics, 16S rRNA sequencing and metabolomics). A intergrade multi-omics analysis was performed to analyze the correlation among gut microbiota, plasma metabolites, and hippocampal gene expression. ResultsHere we found that a 28-day Intermittent fasting (IF) regimen improved cognitive deficits in db/db mice via a microbiota-metabolites-brain axis assessed by behavioral tests and multiple-omics analysis: IF activated AMPK/PGC1α signaling, enhanced mitochondrial biogenesis in hippocampus and elevated genes enriched in hippocampal metabolic function. Moreover, IF re-structured gut microbiota and improved plasma microbial metabolites in relation to diabetes and cognitive function, e.g., serotonin, 3-Indolepropionic acid, and bile acids. Integration of multi-omics data demonstrated strong links between IF-related genes, gut microbiome and metabolites. Furthermore, removal of gut microbiota with antibiotics partly abolished the observed benefits of IF on cognition and hippocampal metabolic function. ConclusionsTaken together, the present study suggests a critical role of gut microbiota in connecting peripheral metabolism with brain function, which could lead to novel interventions against metabolism-implicated neurodegenerative pathophysiologies. Funding SourcesThis work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China.

Liraglutide ameliorates cognitive decline by promoting autophagy via the AMP-activated protein kinase/mammalian target of rapamycin pathway in a streptozotocin-induced mouse model of diabetes

Diabetic cognitive dysfunction has gained widespread attention for its deleterious impact on individuals with diabetes. However, few clinical interventions are available to prevent the disorder. The glucagon-like peptide-1 analog liraglutide exerts neuroprotective effects in several models of neurodegenerative diseases. We investigated the effect of liraglutide pretreatment on diabetes-induced cognitive decline and explored the underlying mechanisms in vivo and in vitro. Liraglutide pretreatment prevented diabetes-induced cognitive impairment as assessed by the Morris Water Maze test, and alleviated neuronal injuries and ultrastructural damage to synapses in the hippocampal CA1 region. Furthermore, liraglutide promoted autophagy as indicated by enhanced expression of the autophagy markers Microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin 1, decreased expression of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. In vitro, liraglutide treatment elevated phosphorylated (p)-AMP-activated protein kinase (AMPK) levels and reduced p-mammalian target of rapamycin (p-mTOR) expression. Additionally, the AMPK inhibitor Compound C exhibited an inhibitory effect on liraglutide-induced increased LC3-II expression and p62 degradation. Liraglutide exhibits neuroprotective effects against diabetes-induced hippocampal neuronal injuries and cognitive impairment by promoting autophagy via the AMPK/mTOR pathway.

Favorable effects of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced diabetic rats

Progression of diabetes mellitus is accompanied by metabolic disorders together with psychological deficits including cognitive dysfunctions. Herein, we used a murine streptozotocin (STZ)-induced diabetes to investigate the beneficial effects of vildagliptin not only on metabolic abnormalities, but also on diabetes-induced cognitive decline. Sixty rats were divided randomly and equally into 2 groups; one remains normal and the other serves as STZ- induced diabetic. Both groups were further divided equally into 2 groups; one received vehicle and the other received oral vildagliptin for 8 weeks. Cognitive behavior was assessed using novel object recognition test. Blood samples were collected to measure metabolic parameters and dipeptidyl peptidase (DPP)-IV activity. Brains were removed and investigated for the levels of inflammatory and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) and tumor necrosis factor-α (TNF-α), in addition to brain-derived neurotrophic factor (BDNF) and relative expression of nuclear factor kappa B (NF-κB)/p65. Treatment of STZ-induced diabetic rats with vildagliptin increased their body weight and corrected diabetes-induced memory and learning impairment. Moreover, vildagliptin significantly decreased serum levels of glucose and lipids (except high density lipoprotein) together with brain MDA, TNF-α, serum DPP-IV activities and NF-κB/p65 gene expression. On the other hand, vildagliptin significantly increased brain BDNF, SOD as well as serum insulin. Results suggested that vildagliptin has a protective role in counteracting both metabolic abnormalities and memory deficits in diabetic rats, possibly via its anti-hyperglycemic, anti-inflammatory, antioxidant effects, together with reduction of brain NF-κB/p65 over expression.

Caloric restriction improves diabetes-induced cognitive deficits by attenuating neurogranin-associated calcium signaling in high-fat diet-fed mice

Diabetes-induced cognitive decline has been recognized in human patients of type 2 diabetes mellitus and mouse model of obesity, but the underlying mechanisms or therapeutic targets are not clearly identified. We investigated the effect of caloric restriction on diabetes-induced memory deficits and searched a molecular mechanism of caloric restriction-mediated neuroprotection. C57BL/6 mice were fed a high-fat diet for 40 weeks and RNA-seq analysis was performed in the hippocampus of high-fat diet-fed mice. To investigate caloric restriction effect on differential expression of genes, mice were fed high-fat diet for 20 weeks and continued on high-fat diet or subjected to caloric restriction (2 g/day) for 12 weeks. High-fat diet-fed mice exhibited insulin resistance, glial activation, blood–brain barrier leakage, and memory deficits, in that we identified neurogranin, a down-regulated gene in high-fat diet-fed mice using RNA-seq analysis; neurogranin regulates Ca2+/calmodulin-dependent synaptic function. Caloric restriction increased insulin sensitivity, reduced high-fat diet-induced blood–brain barrier leakage and glial activation, and improved memory deficit. Furthermore, caloric restriction reversed high-fat diet-induced expression of neurogranin and the activation of Ca2+/calmodulin-dependent protein kinase II and calpain as well as the downstream effectors. Our results suggest that neurogranin is an important factor of high-fat diet-induced memory deficits on which caloric restriction has a therapeutic effect by regulating neurogranin-associated calcium signaling.

Neuroprotective and nootropic activity of Clitorea ternatea Linn.(Fabaceae) leaves on diabetes induced cognitive decline in experimental animals

Purpose:Ethanol extract of Clitorea ternatea (EECT) was evaluated in diabetes-induced cognitive decline rat model for its nootropic and neuroprotective activity.Materials and Methods:Effect on spatial working memory, spatial reference memory and spatial working-reference memory was evaluated by Y maze, Morris water maze and Radial arm maze respectively. Neuroprotective effects of EECT was studied by assaying acetylcholinesterase, lipid peroxide, superoxide dismutase (SOD), total nitric oxide (NO), catalase (CAT) and glutathione (GSH) levels in the brain of diabetic rats.Results:The EECT (200 and 400 mg/kg) was found to cause significant increase in spatial working memory (P < 0.05), spatial reference memory (P < 0.001) and spatial working-reference (P < 0.001) in retention trials on Y maze, Morris water maze and Radial arm maze respectively. Whereas significant decrease in acetylcholinesterase activity (P < 0.05), lipid peroxide (P < 0.001), total NO (P < 0.001) and significant increase in SOD, CAT and GSH levels was observed in animals treated with EECT (200 and 400 mg/kg) compared to diabetic control group.Conclusions:The present data indicates that Clitorea ternatea tenders protection against diabetes induced cognitive decline and merits the need for further studies to elucidate its mode of action.

Inhibition of NF-kappaB activation by Pyrrolidine dithiocarbamate partially attenuates hippocampal MMP-9 activation and improves cognitive deficits in streptozotocin-induced diabetic rats

Matrix metalloproteinase-9 (MMP-9) has been found at significantly increased activity and also contributes to blood–brain barrier degradation in diabetes. Activation of NF-κB pathway is associated with diabetes-induced cognitive impairment, and MMP-9 gene promoter contains a highly conserved motif that matches the NF-κB p65 binding element. No data have been yet provided to show that diabetes-induced cognitive decline is actually associated with increased activity of MMP-9, however, so we sought to understand the potential role of NF-κB-MMP-9 pathway in diabetic rats’ brain. Streptozocin (STZ) was used to induce diabetes in Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an effective NF-κB inhibitor, was administrated to diabetic rats for 6 weeks from the end of diabetes induction. Six weeks later, separate cohorts of rats were tested for cognitive function with Morris water maze task, or euthanized to assess MMP-9 and NF-κB levels in hippocampus. The diabetic rats developed cognitive deficit which was associated with enhanced hippocampal MMP-9 and NF-κB expression. PDTC treatment returned the levels of NF-κB toward their control values and significantly improved diabetes-induced behavioral dysfunction. However, the hippocampal MMP-9 expression triggered by diabetes was only slightly (though significantly) attenuated because MMP-9 protein level in PDTC treated diabetic rats was still higher than that in control rats. Moreover, chronic PDTC treatment did not affect the body weight and plasma glucose levels as compared to the diabetic group, which suggested that PDTC could not ameliorate the diabetic metabolic disorder. In conclusion, these data reveal that diabetes-associated cognitive deficit stems partially from up-regulation of hippocampal MMP-9 via activation of NF-κB signaling pathway.

Clitorea ternatea, a herb from Indian folklore, improves streptozotocin-induced diabetes and diabetes-induced cognitive decline in rats

To study the antidiabetic, neurochemical-antioxidant and cognition protective effects of Clitorea ternatea leaves on a rat model of diabetic cognitive decline. Antidiabetic activity was evaluated by serum glucose and body weight estimation in ethanol extract of Clitorea ternatea (EECT)-treated diabetic rats. Effects of EECT on spatial working memory (SWM) and spatial reference memory (SRM) were evaluated by Y-maze and Morris water maze tests respectively. Neurochemical-antioxidant effects of EECT were studied by acetylcholinesterase assay, and measurements of thiobarbituric acid reactive substances (TBARSs), superoxide dismutase (SOD) and catalase (CAT) levels in diabetic rats. The 200 and 400 mg/kg of EECT showed a significant antidiabetic activity by decreasing serum glucose level (P<0.05, P<0.01), and there was a significant increase in the body weight in 400 mg/kg of EECT-treated diabetic rats (P<0.01). EECT was found to cause significant increases in SWM and SRM in retention trials on Y-maze and Morris water maze respectively (P<0.05, P<0.01). Significant decreases in acetylcholinesterase activity and TBARS level, and significant increase in CAT level were observed in rats treated with 200 and 400 mg/kg of EECT compared with rats in the diabetic control group (P<0.05 or P<0.01). Significant increase was also found in SOD in rats treated with 400 mg/kg of EECT. Clitorea ternatea exhibits antidiabetic and antioxidant activities, offers the protection against diabetes-induced cognitive decline, and warrants the need for further studies to elucidate its mode of action.

Neurovascular Coupling in Cognitive Impairment Associated With Diabetes Mellitus

Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood-brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed.