Linking type 2 diabetes and Alzheimer's disease

Han, Weiping; Li, Cai

doi:10.1073/pnas.1002555107

Cited by 96 publications

(77 citation statements)

References 22 publications

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“…The mice injected with a single high dose of STZ, a nongenetic rodent model mimicking human T1DM, displayed memory impairment, which was demonstrated by decreases in the step-through latency and increases in the number of errors in the passive avoidance test, as well as decreases in the percentage of time spent in the target quadrant in the MWM test, accompanied by elevations of Aβ 1-40 and Aβ 1-42 levels in the brain. The accumulation of Aβ, especially Aβ 1-42 , in the brain may initiate pathogenic cascades mediating neurovascular and neuronal dysfunctions associated with the development of cerebral β-amyloidosis and cognitive decline in patients with diabetes [22,30] . Aβ originates from proteolysis of the APP by the sequential enzymatic actions of BACE1, a β-secretase, and γ-secretase.…”

Section: Pioglitazone Treatment Reduces Brain App and Bace1 Levels Inmentioning

confidence: 99%

Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain β-amyloid through PPARγ activation

et al. 2013

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Aim: To examine the effects of pioglitazone, a PPARγ agonist, on memory performance and brain amyloidogenesis in streptozotocin (STZ)-induced diabetic mice. Methods: ICR male mice were injected with STZ (150 mg/kg, iv) to induce experimental diabetes. Pioglitazone (9 and 18 mg·kg, po) was administered for 6 weeks. Passive avoidance and Morris water maze (MWM) tests were used to evaluate cognitive function. The blood glucose and serum insulin levels were detected using the glucose oxidase method and an ELISA assay, respectively. β-amyloid (Aβ), β-amyloid precursor protein (APP), β-amyloid precursor protein cleaving enzyme 1 (BACE1), NF-κB p65, the receptor for advanced glycation end products (RAGE) and PPARγ in the brains were analyzed using Western blotting assays. Results: The STZ-induced diabetic mice characterized by hyperglycemia and hypoinsulinemia performed poorly in both the passive avoidance and MWM tests, accompanied by increased Aβ 1-40 /Aβ 1-42 , APP, BACE1, NF-κB p65 and RAGE levels and decreased PPARγ level in the hippocampus and cortex. Chronic pioglitazone treatment significantly ameliorated the memory deficits and amyloidogenesis of STZ-induced diabetic mice, and suppressed expression of APP, BACE1, RAGE and NF-κB p65, and activated PPARγ in the hippocampus and cortex. However, pioglitazone did not significantly affect blood glucose and insulin levels. Conclusion: Pioglitazone ameliorates memory deficits in STZ-induced diabetic mice by reducing brain Aβ level via activation of PPARγ, which is independent of its effects on blood glucose and insulin levels. The results suggest that pioglitazone may be used for treating the cognitive dysfunction in type 1 diabetes mellitus.

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Section: Pioglitazone Treatment Reduces Brain App and Bace1 Levels Inmentioning

confidence: 99%

Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain β-amyloid through PPARγ activation

et al. 2013

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“…It is time to try alternative hypotheses and adopt different approaches for the development of AD treatment options. The hypothesis that neurodegeneration originates from metabolic imbalance or overactive immune system is supported by numerous studies including epidemiology studies showing 47,48 that patients with type II diabetes display increased risk of AD. The recent genome wide association studies also identified that cholesterol metabolism and immune system are implicated in the etiology of AD 49,50 .…”

Section: Discussionmentioning

confidence: 88%

Neurodegeneration: Potential Causes, Prevention, and Future Treatment Options

Zhang

2011

Nat Prec

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Here I advance a hypothesis that neurodegeneration is a natural process associated with aging due to the loss of genetic redundancy following a mathematical model R(t) = R 0 (1-αe (βC+γI+δEt)t ), where the calorie intake (C) and immune response (I) play critical roles. The early onset of neurodegenerative diseases such as Alzheimer's disease is due to metabolic imbalance or chronic immune reactions to various infections. Therefore, the potential treatment options for neurodegenerative diseases are to modulate metabolism and immune response.Age related neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) exert tremendous social and economic strain on society. The World Alzheimer Report 2010 estimated that worldwide economic cost of age-related dementia is over $600 billion annually, and predicted it will rise rapidly in the near future. Even though scientific research in academic and industrial settings has made significant progress in understanding the basis of neurodegeneration, the development of disease-modifying treatment options lags behind. The majority of treatments in development for AD funded by public and private sources are based on the β-amyloid cascade hypothesis 1, 2 . However, late-stage clinical trials based on this hypothesis have not been successful, such as Semagacestat (bace 1 inhibitor) 3, 4 from Eli Lilly and earlier immunotherapy from Elan Pharmaceuticals 5 . In addition, there are hundreds of current clinical studies targeting the same pathway by reduction of β-amyloid load or its accumulation. This begs the critical question: will the reduction of β-amyloid burdens result in the slowing-down of neurodegeneration? Here we propose a novel hypothesis regarding the cause of neurodegeneration which implies alterative treatment options. It is imperative for society as a whole to pool resources to solve the urgent needs of an aging worldwide population. Therefore, where and how to use the limited resource becomes an increasingly important question. HYPOTHESISAging is the result of the reduction of genetic redundancy due to accumulated cellular damage from free radicals. These free radicals come from two main sources, metabolic process and immune response, as well as a secondary source, the environment.The proposed mechanism of DNA damage is especially true for neurons, since differentiated cells do not replicate or undergo replication repair and the genetic errors cannot come from DNA replication. In addition, the implied reduction in genetic redundancy not only originates from direct DNA damage, but also comes from damage to other cellular components, as this damage can reduce cell's ability or accuracy to transcribe or translate the genetic information. Two major sources of free radicals, metabolism 6 (mitochondria respiration) and immune response 7 are unavoidable and therefore, life is destined to age.Combining this hypothesis with the free radical theory of aging 8 , the reliability theory of aging 9, 10 and the Gompertz-Makeham 11, 12 law of mortality, we c...

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“…Spontaneous amyloidosis was reported in old individuals, deposits being remarked mainly in kidneys, but also in the different segments of digestive system, lung, heart and adrenal glands [108]. NSY mice as well as ob/ob mice prove recently to be the source of creating of new animal models for simultaneous development and research of Allzheimer's disease and NIDDM [109].…”

Section: Nagoya-shibata-yasuda (Nsy) Mouse Is a Spontaneous Model Of mentioning

confidence: 99%

Development of Improved Animal Models for the Study of Diabetes

Ciobotaru¹

2013

Diabetes Mellitus - Insights and Perspectives

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Linking type 2 diabetes and Alzheimer's disease

Cited by 96 publications

References 22 publications

Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain β-amyloid through PPARγ activation

Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain β-amyloid through PPARγ activation

Neurodegeneration: Potential Causes, Prevention, and Future Treatment Options

Development of Improved Animal Models for the Study of Diabetes

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