Regulation of Diabetes: a Therapeutic Strategy for Alzheimer's Disease?

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aß) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aß plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.

Characterization of Impaired Cerebrovascular Structure in APP/PS1 Mouse Brains.

Alzheimer's disease (AD) is defined by senile plaques, tauopathy and neuronal cell death in specific area of the brain. Recent studies suggest that neurovascular dysfunction may be an integral part of AD pathogenesis, contributing to the onset and development of AD pathologies such as neuronal death, inflammatory response, and breakdown of blood-brain barrier (BBB). In addition, vascular complications caused by age-related metabolic diseases such as diabetes and high blood pressure have high incidence in development of dementia and AD. We previously reported that astrocytes, essential components of BBB, were chronically activated and some deteriorated in the brain of 5xFAD, an amyloid precursor protein/presenilin1 (APP/PS1) transgenic mouse model. Thus, it is rational to investigate if any vascular dysfunction is associated with considerable activation of astrocytes in APP/PS1 mouse model. In this study, we observed that cerebrovascular pathology was associated with large scale of reactive astrocytes and neurodegeneration in an Aß plague-generating mouse model. Using 5xFAD mouse brains, we demonstrate damaged brain vessels and reduced expression of glucose transporter 1 (GLUT1), the main glucose transporter, and a tight junction protein zonula occludens-1 (ZO-1) of cerebrovascular endothelial cells. This vascular pathology was closely associated with astrocytic deterioration and neuronal loss due to buildup of Aß plaques in 5xFAD mouse brains.

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes.

In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes. The present study investigated the role of p53 in astrocyte and neuronal toxicity using in-vitro and in-vivo ischemic stroke models. We showed that p53 is activated in ischemic brains and in oxygen-glucose deprivation (OGD)-induced cell death in neurons and astrocytes. Inhibition of p53 activity using either pifithrin-α or small interference RNA interference reduced OGD-induced cell death and pifithrin-α reversed OGD-induced impairment of glutamate uptake in astrocytes, suggesting that p53 might play a key role in mediating neurotoxicity and gliotoxicity in ischemic brain injury. This study shows that p53 is activated in astrocytes during ischemia and that inhibition of the activity of this molecule prevents not only OGD-induced neuronal and astrocytic death but also astrocyte activation and impaired glutamate uptake. These findings suggest that p53 may be a valuable therapeutic target in ischemic brain injury.