There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy ...people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 PS1 mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in ...physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N‐ and C‐terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single‐channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology.
Key points
The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known.
TRPV4 is activated by a bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose‐dependent manner, in both a primary and a heterologous expression system.
Activation of TRPV4 by LPA18:1 requires residues in the N‐ and C‐termini of the ion channel.
Single‐channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single‐channel amplitude.
Distinct single‐channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions.
figure legend TRPV4 is differentially activated by distinct ligands. Lysophosphatidic acid 18:1 (LPA18:1) activates TRPV4 with a larger conductance as compared to lysophosphatidylcholine 18:1 (LPC18:1). These different modes of activation can lead to differences in cell excitability.
Objective
The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the ...accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia.
Background
An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease‐modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits.
Updated Hypothesis
It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid‐only and pre‐amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti‐Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease‐modifying Aβ therapies.
Major Challenges for the Hypothesis
Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late‐onset AD.
Linkage to Other Major Theories
The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co‐pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.
Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates ...key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonstrated increased sensitivity of cortical pyramidal cells to release glutamate from their striatal nerve terminals driving striatal circuits, a correlative finding of the cortical motor hyperexcitability of RLS patients. It was also found that BID in rodents leads to changes in the adenosinergic system, a downregulation of the inhibitory adenosine A
receptors (A
Rs) and upregulation of the excitatory adenosine A
receptors (A
Rs). It was then hypothesized, but not proven, that the BID-induced increased sensitivity of cortico-striatal glutamatergic terminals could be induced by a change in A
R/A
R stoichiometry in favor of A
Rs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A
Rs and A
Rs in cortico-striatal and thalamo-striatal glutamatergic terminals (labeled with vesicular glutamate transporters VGLUT1 and VGLUT2, respectively) of control and BID rats. It could be demonstrated that BID (determined by measuring transferrin receptor density in the brain) is associated with a selective decrease in the A
R/A
R ratio in VGLUT1 positive-striatal terminals.
Con base en una documentación rica e inédita, este artículo busca establecer los cambios en las relaciones laborales de los pueblos de indios o reducciones con el surgimiento y consolidación de ...estancias ganaderas y obrajes privados en las inmediaciones, y la disminución drástica de la población indígena en la meseta de Bombón entre 1667 y 1677 (Andes centrales). Se discuten temas de la historia laboral vigentes en la historiografía peruana y latinoamericana como el trabajo libre y el compulsivo, la mita, el yanaconaje, el peonaje y las reducciones o pueblos de indios. Este estudio encuentra que en las nuevas condiciones los pueblos de indios siguen siendo importantes, pero, con la aparición de mecanismos coercitivos individuales, han dejado de ser imprescindibles para reclutar, retener y remunerar a los trabajadores de las haciendas y el obraje.
Motivated by algorithmic information theory, the problem of program discovery can help find candidates of underlying generative mechanisms of natural and artificial phenomena. The uncomputability of ...such inverse problem, however, significantly restricts a wider application of exhaustive methods. Here we present a proof of concept of an approach based on IMP, a high-level imperative programming language. Its main advantage is that conceptually complex computational routines are more succinctly expressed, unlike lower-level models such as Turing machines or cellular automata. We investigate if a more expressive higher-level programming language can be more efficient at generating approximations to algorithmic complexity of recursive functions.
•We explore an inverse problem for model discovery based on principles of algorithmic information.•The method can help find candidates of underlying generative mechanisms and first principles.•A proof of concept based on IMP, a high-level imperative programming language, is provided.•IMP expressions are succinct, unlike lower-level models such as formal automata.•We investigate if a more expressive higher-level programming language can be more efficient.
Summary Background Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the ...accumulation of Aβ in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. Methods Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18–60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition. Findings We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively.18 F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. Interpretation These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease. Funding Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of ...experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.
Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules ...is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences. Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.
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