Advances in genetic and molecular understanding of Alzheimer\u27s disease

Alzheimer\u27s disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine

Decision events in the germinal centre: the role of ACKR4

Murine atypical chemokine receptor 4, ACKR4, which binds to chemokines CCL19, CCL21 and CCL25, is expressed specifically in germinal centre (GC) B cells and in a layer of stromal cells surrounding the splenic marginal zone. Although ACKR4 is unable to signal as classical GPCRs, it creates gradients of its ligands. It is shown here that ACKR4 deficiency in the stroma causes infiltration of naïve B cells into the GC area. ACKR4 deficiency in the B cells causes dysregulation of the intragerminal centre distribution, with enlarged light zones and reduced dark zones when compared to ACKR4-competent mice. This skewed GC distribution is caused by the inability of ACKR4-deficient B cells to downregulate c-Myc, as they receive increased signalling though the CCR7- p-Akt - c-Myc signalling pathway. Moreover, ACKR4-deficient mice contain elevated numbers of memory B cells (MBC) in the distant lymphoid organs. MBCs are retained in the draining lymph node (drLN) by the presence of a CCL19/21 gradient towards the subcapsular sinus (SCS). When this gradient is absent, as occurs in ACKR4-deficient mice, MBCs escape the drLN easier through the SCS and appear in other sites in elevated numbers. Together, this shows a new role for ACKR4 in the GC response and in the migration of GC-derived MBCs out of the follicle and the drLN

Fecal sacs attract insects to the nest and provoke an activation of the immune system of nestlings

Background: Nest sanitation is a widespread but rarely studied behavior in birds. The most common form of nest sanitation behavior, the removal of nestling feces, has focused the discussion about which selective pressures determine this behavior. The parasitism hypothesis, which states that nestling fecal sacs attract parasites that negatively affect breeding birds, was proposed 40 years ago and is frequently cited as a demonstrated fact. But, to our knowledge, there is no previous experimental test of this hypothesis. Results: We carried out three different experiments to investigate the parasitism hypothesis. First, we used commercial McPhail traps to test for the potential attraction effect of nestling feces alone on flying insects. We found that traps with fecal sacs attracted significantly more flies (Order Diptera), but not ectoparasites, than the two control situations. Second, we used artificial blackbird (Turdus merula) nests to investigate the combined attraction effect of feces and nest materials on arthropods (not only flying insects). Flies, again, were the only group of arthropods significantly attracted by fecal sacs. We did not detect an effect on ectoparasites. Third, we used active blackbird nests to investigate the potential effect of nestling feces in ecto- and endoparasite loads in real nestlings. The presence of fecal sacs near blackbird nestlings did not increase the number of louse flies or chewing lice, and unexpectedly reduced the number of nests infested with mites. The endoparasite prevalence was also not affected. In contrast, feces provoked an activation of the immune system as the H/L ratio of nestlings living near excrements was significantly higher than those kept under the two control treatments. Conclusions: Surprisingly, our findings do not support the parasitism hypothesis, which suggests that parasites are not the main reason for fecal sac removal. In contrast, the attraction of flies to nestling feces, the elevation of the immune response of chicks, and the recently described antimicrobial function of the mucous covering of fecal sacs suggest that microorganisms could be responsible of this important form of parental care behavior (microbial hypothesisPeer reviewe

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

AbstractGene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.</jats:p

Sleep Diplomacy: an Approach to Boosting global brain health

Sleep diplomacy highlights the urgent need to address the widespread issue of sleep deprivation and its detrimental effects on overall health, particularly brain health and healthy ageing. By providing practical advice on sleep hygiene, healthy schedules, and light exposure, sleep diplomacy aims to promote a comprehensive approach to well-being. Despite the well-established importance of sleep for optimal cognitive function, emotional regulation, and physical abilities, it is often neglected in public and medical recommendations. Our proposed concept of sleep diplomacy also offers practical recommendations to address sleep issues in various settings and populations

Subjective and objective sleep quality in elderly individuals: The role of psychogeriatric evaluation

[EN] Aging affects sleep and sleep problems are common in older individuals. However, the relationship between objective and subjective tools for analysing sleep and psycho-geriatric variables have not been tested in institutionalised older individuals. This work analyses sleep quality by using actigraphy as an objective tool and validates the Athens and Oviedo sleep questionnaires in octogenarian elderly individuals as subjective scales of sleep perception. All patients wore an actigraph device for one week and then completed the Athens and Oviedo clinical sleep-evaluation questionnaires. Morning cortisol levels in blood plasma and saliva samples were also measured to assess the association between objective and reported sleep patterns. Age, gender, and psycho-geriatric evaluations, including Barthel, Tinetti, and Mini-Mental scale measurements were analysed as variables with the potential to confound the strength of any such associations. There was a significant inverse correlation between the number of awakenings and the time spent awake during night assessed by actigraphy and the total Oviedo questionnaire score, but no significant associations for the other parameters. The blood cortisol concentration appears to be a marker of insomnia related to sleep times of less than four hours and diagnosis of insomnia based on Athens scale and thus, represents a potential marker for sleep interventions.This work was funded with the 2016 University of Valencia departmental research grant awarded to Prof. Dr. O. Cauli (445-inf85).Ibanez-Del Valle, V.; Silva, J.; Castello-Domenech, A.; Martinez-Martinez, M.; Verdejo, Y.; Sanantonio-Camps, L.; Cauli, O. (2018). Subjective and objective sleep quality in elderly individuals: The role of psychogeriatric evaluation. Archives of Gerontology and Geriatrics. 76:221-226. https://doi.org/10.1016/j.archger.2018.03.010S2212267