The anthracycline doxorubicin (DOX) is widely used in chemotherapy due to its efficacy in fighting a wide range of cancers such as carcinomas, sarcomas and hematological cancers. Despite extensive clinical utilization, the mechanisms of action of DOX remain under intense debate. A growing body of evidence supports the view that this drug can be a double-edge sword. Indeed, injury to nontargeted tissues often complicates cancer treatment by limiting therapeutic dosages of DOX and diminishing the quality of patients' life during and after DOX treatment. The literature shows that the heart is a preferential target of DOX toxicity. However, this anticancer drug also affects other organs like the brain, kidney and liver. This review is mainly devoted to discuss the mechanisms underlying not only DOX beneficial effects but also its toxic outcomes. Additionally, clinical studies focusing the therapeutic efficacy and side effects of DOX treatment will be discussed. Finally, some potential strategies to attenuate DOX-induced toxicity will be debated.

No abstract

The endoplasmic reticulum (ER) is the principal organelle responsible for the proper folding/processing of nascent proteins and perturbed ER function leads to a state known as ER stress. Mammalian cells try to overcome ER stress through a set of protein signaling pathways and transcription factors termed the unfolded protein response (UPR). However, under unresolvable ER stress conditions, the UPR is hyperactivated inducing cell dysfunction and death. The accumulation of misfolded proteins in the brain of Alzheimer's disease (AD) patients suggests that alterations in ER homeostasis might be implicated in the neurodegenerative events that characterize this disorder. This review discusses the involvement of ER stress in the pathogenesis of AD, focusing the processing and trafficking of the AD-related amyloid precursor protein (APP) during disease development. The potential role of ER as a therapeutic target in AD will also be debated.

No abstract

According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.

Evidence shows that diabetes increases the risk of developing Alzheimer’s disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-AD), and WT mice fed 20% sucrose-sweetened water for 7 months. Polarography, spectrophotometry, fluorimetry, high-performance liquid chromatography, and electron microscopy were used to evaluate mitochondrial function, oxidative status, and ultrastructure. Western blotting was performed to determine the AD pathogenic protein levels. Sucrose intake caused metabolic alterations like those found in type 2 diabetes. Mitochondria from 3xTg-AD and sucrose-treated WT mice presented a similar impairment of the respiratory chain and phosphorylation system, decreased capacity to accumulate calcium, ultrastructural abnormalities, and oxidative imbalance. Interestingly, sucrose-treated WT mice presented a significant increase in amyloid β protein levels, a hallmark of AD. These results show that in mice, the metabolic alterations associated to diabetes contribute to the development of AD-like pathologic features.

Insulin, long known as an important regulator of blood glucose levels, plays important and multifaceted roles in the brain. It has been reported that insulin is an important neuromodulator, contributing to several neurobiological processes in particular energy homeostasis and cognition. Dysregulation of insulin signaling has been linked to aging and metabolic and neurodegenerative disorders. The first part of this review is devoted to discussion of the critical role of insulin signaling in normal brain function. Then the involvement of impaired insulin signaling in the pathophysiology of diabetes, Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis will be discussed. Finally, the potential therapeutic effect of insulin and insulin sensitizers will be examined.

No abstract