The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress?

Among the long list of age-related complications, Alzheimer’s disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.     

Can ultrasound be used to stimulate nerve tissue?

Background  

The stimulation of nerve or cortical tissue by magnetic induction is a relatively new tool for the non-invasive study of the brain and nervous system. Transcranial magnetic stimulation (TMS), for example, has been used for the functional mapping of the motor cortex and may have potential for treating a variety of brain disorders.     

Modifying mosquitoes to suppress disease transmission: Is the long wait over?

For more than 50 years it has been a dream of medical entomologists and public health workers to control diseases like malaria and dengue fever by modifying, through genetics and other methods, the arthropods that transmit them to humans. A brief synopsis of the history of these efforts as applied to mosquitoes is presented; none proved to be effective in reducing disease prevalence. Only in the last few years have novel approaches been developed or proposed that indicate the long wait may be over. Three recent developments are particularly promising: CRISPR-Cas9 driven genetic modification, shifting naturally occurring allele frequencies, and microbe-based modifications. The last is the furthest along in implementation. Dengue fever incidence has been reduced between 40% and 96% in 4 different regions of the world where Wolbachia-infected Aedes aegypti have been established in the field. It is not yet clear how sustainable such control programs will prove to be, but there is good reason for optimism. In light of this, the time is ripe for reinvigorated research on vectors, especially genetics. Vector-borne diseases primarily affect under-developed countries and thus have not received the attention they deserve from wealthier countries with well-developed and funded biomedical research establishments.     

The somatopause: to treat or not to treat?

There is much evidence that some aspects of ageing are similar to those observed in selective hormone deficiencies during adulthood. Replacement therapy in hypogonadism and/or growth hormone (GH) deficiency in adulthood is very successful in reversing the related clinical symptomatology. However, preliminary studies of GH treatment in the normal elderly have been largely disappointing: an increase in muscle mass is only accompanied by improved muscle strength if exercise is also increased during this period. No real benefit of GH therapy, additional to that of exercise, has been reported. Epidemiological studies indicate a relationship between high-normal insulin-like growth factor-I levels and cancer development. No definitive answers can presently be given regarding the safety of long-term GH therapy in otherwise healthy individuals during the somatopause.     

Atrial fibrillation: to map or not to map?

Isolation of the pulmonary veins may be an effective treatment modality for eliminating atrial fibrillation (AF) episodes but unfortunately not for all patients. When ablative therapy fails, it is assumed that AF has progressed from a trigger-driven to a substrate-mediated arrhythmia. The effect of radiofrequency ablation on persistent AF can be attributed to various mechanisms, including elimination of the trigger, modification of the arrhythmogenic substrate, interruption of crucial pathways of conduction, atrial debulking, or atrial denervation. This review discusses the possible effects of pulmonary vein isolation on the fibrillatory process and the necessity of cardiac mapping in order to comprehend the mechanisms of AF in the individual patient and to select the optimal treatment modality.     

Allergy to penicillin: fable or fact?

OBJECTIVE--To assess whether, on the basis of one blood test, penicillin allergy might be excluded sufficiently for general practitioners to give oral penicillin to patients claiming a history of penicillin allergy. DESIGN--Prospective study of patients referred by general practitioners. SETTING--Outpatient allergy clinic in a district general hospital. PATIENTS--175 referred patients who gave a history of immediate type reaction to penicillin, of whom 144 attended as requested and 132 completed the investigations. MAIN OUTCOME MEASURES--History and examination, serum radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin, and oral challenge with penicillin. RESULTS--Of 132 patients, four were confirmed to have penicillin allergy by the radioallergosorbent test and 128 had an oral penicillin challenge without ill effect. CONCLUSIONS--Most patients who gave a history of penicillin allergy are not so allergic, and their actual allergic state should be substantiated whenever feasible. For patients reporting minor or vague reactions negative findings with a radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin provide sufficient evidence to give oral penicillin safely.     

How to regulate a gene: to repress or to activate?

Gene-expression responses to an input can depend on growth conditions; in this issue, Sasson et al. (2012) show that this dependence is lower when the input results in a high degree of promoter occupancy.     

Cancer immunotherapy: simply cell biology?

There is a clear need for improved cancer therapy and survival rates. Effective immunotherapy would be the treatment modality of choice from several viewpoints, and dendritic cell (DC)-based immunotherapy is emerging as the most promising approach to cancer immunotherapy. However, the plethora of approaches to DC-based cancer therapy now threatens to impede the development of an effective immunotherapy regime, as competing egos and commercial interests masquerade as scientific rigour. Here, I argue that the current controversies regarding the numerous approaches reflect the paucity of our immunological understanding, and present a simple cell biological analysis that defines the rationale for the development of effective cancer immunotherapy.     

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be 'blind' to tumours, thereby challenging the theory of immune surveillance.     

Eye-hand coordination: eye to hand or hand to eye?

Single-unit recording has revealed both hand and eye movement-related activity in the parietal cortex of the macaque monkey. These experiments, as well as neuropsychological studies, are unravelling the complex nature of how the eye and the hand work together in the control of visually guided movements.     

Adaptation to stress in yeast: to translate or not?

For most eukaryotic organisms, including Saccharomyces cerevisiae, the rapid inhibition of protein synthesis forms part of a response to stress. In order to balance the changing conditions, precise stress-specific alterations to the cell's proteome are required. Therefore, in the background of a global down-regulation in protein synthesis, specific proteins are induced. Given the level of plasticity required to enable stress-specific alterations of this kind, it is surprising that the mechanisms of translational regulation are not more diverse. In the present review, we summarize the impact of stress on translation initiation, highlighting both the similarities and distinctions between various stress responses. Finally, we speculate as to how yeast cells generate stress-responsive programmes of protein production when regulation is focused on the same steps in the translation pathway.     

Myosins in melanocytes: to move or not to move?

The actin network has been implicated in the intracellular transport and positioning of the melanosomes, organelles that are specialized in the biosynthesis and the storage of melanin. It contributes also to molecular mechanisms that underlie the intracellular membrane dynamics and thereby can control the biogenesis of melanosomes. Two mechanisms for actin-based movements have been identified: one is dependent on the motors associated to actin namely the myosins; the other is dependent on actin polymerization. This review will focus on to the role of the actin cytoskeleton and myosins in the transport and in the biogenesis of melanosomes. Myosins involved in membrane traffic are largely seen as transporters of organelles or membrane vesicles containing cargos along the actin networks. Yet increasing evidence suggests that some of the myosins contribute to the dynamics of internal membrane by using other mechanisms. The role of the myosins and the different molecular mechanisms by which they contribute or may contribute to the distribution, the movement and the biogenesis of the melanosomes in epidermal melanocytes and retinal pigmented epithelial (RPE) cells will be discussed.     

Myosins in melanocytes: to move or not to move?

The actin network has been implicated in the intracellular transport and positioning of the melanosomes, organelles that are specialized in the biosynthesis and the storage of melanin. It contributes also to molecular mechanisms that underlie the intracellular membrane dynamics and thereby can control the biogenesis of melanosomes. Two mechanisms for actin‐based movements have been identified: one is dependent on the motors associated to actin namely the myosins; the other is dependent on actin polymerization. This review will focus on to the role of the actin cytoskeleton and myosins in the transport and in the biogenesis of melanosomes. Myosins involved in membrane traffic are largely seen as transporters of organelles or membrane vesicles containing cargos along the actin networks. Yet increasing evidence suggests that some of the myosins contribute to the dynamics of internal membrane by using other mechanisms. The role of the myosins and the different molecular mechanisms by which they contribute or may contribute to the distribution, the movement and the biogenesis of the melanosomes in epidermal melanocytes and retinal pigmented epithelial (RPE) cells will be discussed.