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.

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.

The presence of age-related comorbidities prone elderly patients to the phenomenon of polypharmacy and consequently to a higher risk of nonadherence. Thus, this paper aims to characterize the medication consumption profile and explore the relationship of beliefs and daily medication management on medication adherence by home-dwelling polymedicated elderly people. A questionnaire on adherence, managing, and beliefs of medicines was applied to polymedicated patients with ≥65 years old, in primary care centers of the central region of Portugal. Of the 1089 participants, 47.7% were considered nonadherent. Forgetfulness (38.8%), difficulties in managing medication (14.3%), concerns with side effects (10.7%), and the price of medication (9.2%) were pointed as relevant medication nonadherence-related factors. It was observed that patients who had difficulties managing medicines, common forgetfulness, concerns with side effects, doubting the need for the medication, considered prices expensive, and had a lack of trust for some medicines had a higher risk of being nonadherent. This study provides relevant information concerning the daily routine and management of medicines that can be useful to the development of educational strategies to promote health literacy and improve medication adherence in polymedicated home-dwelling elderly.

Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.

Purpose: The complex combination of medicines associated with age-related physiological alterations leads older adults to experience drug-related problems (DRPs). The goal of this study was to review the frequency and type of DRPs and DRP risk factors in home-dwelling older adults. Methods: A MEDLINE PubMed and EMBASE scientific databases search was performed. Articles published from January 2000 through December 2018 reporting DRPs in home-dwelling older adults were included. Findings: From 668 articles screened, 13 met the inclusion criteria and were included in this study. Overall, the studies included 8935 home-dwelling patients. The mean number of DRPs per patient observed was 4.16 (1.37e10). The main causes of DRPs were "drug selection" (51.41%), "dose selection" (11.62%), and "patient related" (10.70%) problems. The drug classes more frequently associated with DRPs were "cardiovascular system," "alimentary tract and metabolism," and "nervous system," and they represented 32.1%, 29.4%, and 16.5% of all drug selection problems, respectively. Respiratory system medicines accounted for 6.65% of all DRPs, of which "patient related" problems accounted for 97.28%. Implications: Despite the heterogeneity of methodology of the included studies and the heterogeneity of tools used to identify DRPs, this analysis clearly shows the high prevalence of DRPs in home-dwelling older adults and highlights the need for interventions to improve medicine use in this population. This work also provides useful information for the development of strategies to improve medication use in home-dwelling older adults.