Alzheimer disease(AD) and typeⅡdiabetes mellitus(DM2) are the most common disease in aging people,with β-amyloid and amylin accumulation respectively.Studies have shown more and more correlations between these two d...Alzheimer disease(AD) and typeⅡdiabetes mellitus(DM2) are the most common disease in aging people,with β-amyloid and amylin accumulation respectively.Studies have shown more and more correlations between these two diseases,and amylin oligomerization in the brain provided a novel risk target for developing AD.Although cumulative studies reported that amylin aggregation induced cytotoxicity in pancreatic beta cells by altering Ca2+homeostasis,fewer studies investigated the effect of amylin on hippocampal neuron.To address this question,it was investigated the effect of amylin on primary cultured rat hippocampal neurons by calcium imaging and whole-cell patch clamp recording in this study,while the results revealed that human amylin(hAmylin) but not rat amylin or pramlintide(hAmylin analgue) produced a rapid increase in intracellular calcium in a dose dependent manner.This effect relied on extracellular calcium and not abolished by amylin receptor antagonist AC187.Additionally,the calcium increase induced by hAmylin was dependent onvoltage-gated Ca2+channels,especially L-type Ca2+channel activation.In whole-cell recording hAmylin could depolarize membrane potential and increase the cell exitability.Moreover,application of transient receptor potential vanilloid(TRPV) antagonist ruthenium red could abolish part of the intracellular calcium increase.Single cell RT-PCR revealed that TRPV4 mRNA expressed in most of the reactive neuron and selective TRPV4 antagonist HC067047 inhibited the intacellular calcium increasing.These results indicated that hAmylin aggregation precipitating on the neuron membrane activated TRPV4 channels and then triggered membrane voltage gated calcium channel opening followed by membrane depolarization,expressing that TRPV4 is a key molecular target for the cytotoxic effect of hAmylin on cultured neurons.展开更多
The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and cosecreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, ...The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and cosecreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20 G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.展开更多
Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid po...Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.展开更多
文摘Alzheimer disease(AD) and typeⅡdiabetes mellitus(DM2) are the most common disease in aging people,with β-amyloid and amylin accumulation respectively.Studies have shown more and more correlations between these two diseases,and amylin oligomerization in the brain provided a novel risk target for developing AD.Although cumulative studies reported that amylin aggregation induced cytotoxicity in pancreatic beta cells by altering Ca2+homeostasis,fewer studies investigated the effect of amylin on hippocampal neuron.To address this question,it was investigated the effect of amylin on primary cultured rat hippocampal neurons by calcium imaging and whole-cell patch clamp recording in this study,while the results revealed that human amylin(hAmylin) but not rat amylin or pramlintide(hAmylin analgue) produced a rapid increase in intracellular calcium in a dose dependent manner.This effect relied on extracellular calcium and not abolished by amylin receptor antagonist AC187.Additionally,the calcium increase induced by hAmylin was dependent onvoltage-gated Ca2+channels,especially L-type Ca2+channel activation.In whole-cell recording hAmylin could depolarize membrane potential and increase the cell exitability.Moreover,application of transient receptor potential vanilloid(TRPV) antagonist ruthenium red could abolish part of the intracellular calcium increase.Single cell RT-PCR revealed that TRPV4 mRNA expressed in most of the reactive neuron and selective TRPV4 antagonist HC067047 inhibited the intacellular calcium increasing.These results indicated that hAmylin aggregation precipitating on the neuron membrane activated TRPV4 channels and then triggered membrane voltage gated calcium channel opening followed by membrane depolarization,expressing that TRPV4 is a key molecular target for the cytotoxic effect of hAmylin on cultured neurons.
文摘The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and cosecreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20 G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.
基金supported by The Mike Hogg FundBaylor College of Medicine Medical Scientist Training Program,NICHD R01HD099252(to RJP)and R01HD098131(to RJP)the NHLBI T32 HL092332(to ASB)。
文摘Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.
