Perirhinal Cortex Neuronal Activity is Actively Related to Working Memory in the Macaque

Lesion studies suggest that the perirhinai cortex plays a role in object recognition memory. To analyze its role, we recorded the activity of single neurons in the perirhinal cortex in a rhesus monkey (Macaca mulatta) performing a delayed matching-to-sample task with up to four intervening stimuli. Certain neurons (40 of 90 analyzed) showed a smaller response to an image when it was shown the second time within a trial (as a match image) than when it had been shown (as a sample image) the first time. A new finding was that the perirhinal cortex neurons were actively reset between trials: when a particular image was shown as a sample on a succeeding trial, the response was much larger than when it had been shown as a match image a short time previously on the previous trial. This resetting between trials appears to reflect the operation of an active working memory process rather than a passive temporal decay in a neuronal response. The results thus provide evidence that the perirhinal cortex plays an active role in visual working memory, perhaps in association with other brain areas such as the prefrontal cortex

Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide analogues as novel treatments for Alzheimer's and Parkinson's disease

Type 2 diabetes is a risk factor for developing chronic neurodegenerative disorders such as Alzheimer's disease (AD) or Parkinson's disease (PD). The underlying mechanism appears to be insulin desensitization in the brain. A range of glucagon-like peptide 1 (GLP-1) mimetics and glucose-dependent insulinotropic polypeptide (GIP) analogues initially designed to treat diabetes protected transgenic animals that model AD and toxin-based animal models of PD. Novel dual GLP-1/GIP analogues also show good neuroprotective effects. On the basis of these findings, first clinical trials have been conducted. In a pilot study on patients with AD, the GLP-1 analogue liraglutide showed good protective effects in 18 F-fluorodeoxyglucose (18 F-FDG)-PET brain imaging. It was found that the disease-related decay of brain activity had been completely stopped by the drug. In a pilot study in patients with PD, the GLP-1 mimetic exendin-4 showed good protection from motor and cognitive impairments. These results demonstrate the potential of developing disease-modifying treatments for AD and PD

Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models

Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson’ disease. Novel dual GLP-1/GIP receptor agonists have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the blood –brain barrier. They show clear neuroprotective effects by reducing inflammation and oxidative stress and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, dopaminergic neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics

Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease

Type 2 diabetes is a risk factor for developing Alzheimer’s disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common – they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid

Approach for Evaluating Changeable Production Systems in a Battery Module Production Use Case

Volatile markets continue to complicate manufacturing companies’ production system design, leading to efficiency losses due to imperfect system setups. In such a market environment, a perfect system setup cannot be achieved. Therefore, changeable production systems that cope with immanent uncertainty gain interest in research and industry. For several decades, changeable production systems have been in the research and development stage. The advantages and disadvantages are well investigated. So far, however, they have gained only limited acceptance in industry. One of the reasons is the difficult evaluation of the benefits. Existing investment calculation methods either neglect many effects of changeability, such as easier adaptation to unpredictable events, or are too complex and therefore too time-consuming to become standard. Thus, a practical evaluation method is needed that considers these changeability aspects. This paper deviates the industry requirements regarding an evaluation method based on an industry survey and develops a practical approach for an evaluation method for a changeable production system considering monetary and non-monetary aspects. The approach is characterized by a calculation that is as accurate as possible considering the existing input factors. The method shows that changeable production systems excel in environments with frequent need for adaptation. The approach is applied to a battery module assembly in the ARENA2036 research campus

Corrosion Behavior of an Additively Manufactured Functionally Graded Material

Dissimilar metal welds (DMW) combine the high strength and cost benefits of ferritic stainless steels with the high corrosion resistance of austenitic steels, and are thus commonly used in different types of power plants. However, due to the abrupt change in properties, these joints are susceptible to premature failure. Work pieces with a smooth transition in composition and/or properties are referred to as "functionally graded materials" (FGM). When used as transition joints, FGM can enhance the lifetime of certain components. In the present study, the FGM were manufactured by using wire arc additive manufacturing employing cold-wire gas metal arc welding. Since the corrosion resistance of such FGM are still unknown, the corrosion properties of the FGM work piece were compared to those of a DMW work piece by means of electrochemical analysis using potentiodynamic polarization and a salt spray test. The FGM showed a 24 % lower average corrosion rate compared to the reference piece and no signs of pitting or galvanic corrosion. This shows the potential of FGM and further research should be carried out

GLP-1 receptor agonists show neuroprotective effects in animal models of diabetes

Enzyme-resistant receptor agonists of the incretin hormone glucagon-like peptide-1 (GLP-1) have shown positive therapeutic effects in people with type 2 diabetes mellitus (T2DM). T2DM has detrimental effects on brain function and impairment of cognition and memory formation has been described. One of the underlying mechanisms is most likely insulin de-sensitization in the brain, as insulin improves cognitive impairments and enhances learning. Treatment with GLP-1 receptor agonists improves memory formation and impairment of synaptic plasticity observed in animal models of diabetes-obesity. Furthermore, it has been shown that diabetes impairs growth factor signalling in the brain and reduces energy utilization in the cortex. Inflammation and apoptotic signalling was also increased. Treatment with GLP-1 receptor agonists improved neuronal growth and repair and reduced inflammation and apoptosis as well as oxidative stress. In comparison with the diabetes drug metformin, GLP-1 receptor agonists were able to improve glycemic control and reverse brain impairments, whereas metformin only normalized blood glucose levels. Clinical studies in non-diabetic patients with neurodegenerative disorders showed neuroprotective effects following administration with GLP-1 receptor agonists, demonstrating that neuroprotective effects are independent of blood glucose levels

A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10 nmol/kg ip.) once-daily for 14 days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1Ser1101 levels and phospho-AktSer473 up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD

Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells

Growing evidence suggests that agonists of glucagon-like peptide (GLP-1) receptor exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration, and, recently, a pilot clinical trial of Liraglutide in Alzheimer's disease patients showed improvements in cerebral glucose consumption that signifies disease progression. However, the exact underlying mechanism of action remains unclear. Chronic endoplasmic reticulum (ER) stress has recently emerged as a mechanism for neuronal injury, rendering it a potent therapeutic target for acute and chronic neurodegenerative disorders. Here, we investigate the neuroprotective effects of Liraglutide along with the signalling network against prolong ER stress and autophagy impairments induced by the non-competitive inhibitor of sarco/ER Ca2+-ATPase, thapsigargin. We show that Liraglutide modulates the ER stress response and elicits ER proteostasis and autophagy machinery homeostasis in human SH-SY5Y neuroblastoma cell line. These effects correlate with resolution of hyper-activity of the antioxidant Nrf2 factor and restoration of the impaired cell viability and proliferation. Mechanistically, Liraglutide engages Akt and signal transducer and activator of transcription 3 (STAT3) signalling to favour adaptive responses and shift cell fate from apoptosis to survival under chronic stress conditions in SH-SY5Y cells