Current and Near-Future Treatment of Alzheimer's Disease

: Recent findings have improved our understanding of the multifactorial nature of AD. While in early, asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, in the later stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include: increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, one should use combination therapies consisting of drugs that rectify several of the above-mentioned dysfunctions. It should be noted that many of widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, also have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is a real hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel method to enhance health and treat AD.

Longitudinal Profiling in Phenotypic Metric of Aging: Insights From the Baltimore Longitudinal Study of Aging

It remains challenging to quantify the pace of aging across lifespan due to lack of comprehensive longitudinal measurements across wide range of age. In Baltimore Longitudinal Study of Aging, we have measured the longitudinal trajectories of more than 30 phenotypes across four pre-identified domain - body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity, among participants with age between 20+ and 90+. We implemented a two-stage approach to summarize the longitudinal trajectories of these phenotypes across four domains into a summarized score. We demonstrated that higher summarized score (denoting for slower longitudinal phenotypic decline) is associated with slower decline in both cognitive and physical functions, across different stages of adulthood. Our results imply that deep longitudinal profiling contains rich information and may potentially replace diseases as an early endpoint in trials targeting at aging. Further, understanding the underpinning of longitudinal phenotypic trajectories may provide clues to the biological mechanisms of aging.

WTS-1/LATS regulates endocytic recycling by restraining F-actin assembly in a synergistic manner

The disruption of endosomal actin architecture negatively affects endocytic recycling. However, the underlying homeostatic mechanisms that regulate actin organization during recycling remain unclear. In this study, we identified a synergistic endosomal actin assembly restricting mechanism in C. elegans involving WTS-1/LATS kinase, which is a core component of the Hippo pathway. WTS-1 resides on the sorting endosomes and colocalizes with the actin polymerization regulator PTRN-1/CAMSAPs. We observed an increase in PTRN-1-labeled structures in WTS-1-deficient cells, indicating that WTS-1 can limit the endosomal localization of PTRN-1. Accordingly, the actin overaccumulation phenotype in WTS-1-depleted cells was mitigated by the associated PTRN-1 loss. We further demonstrated that recycling defects and actin overaccumulation in WTS-1-deficient cells were reduced by the overexpression of constitutively active UNC-60A/cofilin(S3A), which aligns with the role of LATS as a positive regulator of cofilin activity. Altogether, our data confirmed previous findings, and we proposed an additional model: WTS-1 acts alongside the UNC-60A/cofilin-mediated actin disassembly to restrict the assembly of endosomal F-actin by curbing PTRN-1 dwelling on endosomes, preserving recycling transport.

The role of clathrin in exocytosis and the mutual regulation of endo- and exocytosis in plant cells

Within the plant endomembrane system, the vesicle coat protein clathrin localizes to the plasma membrane (PM) and the trans-Golgi Network/Early Endosome (TGN/EE). While the role of clathrin as a major component of endocytosis at the PM is well established, its function at TGN/EE, possibly in exocytosis or the vacuolar pathway, is a matter of debate. This shared function of clathrin also opens a question whether plant cells possess a homeostatic mechanisms that balance rates of opposite trafficking routes, such as endo- and exocytosis. Here we address these questions using lines inducibly silencing CLATHRIN HEAVY CHAIN (CHC). We find a relocation of exocytic soluble and integral membrane protein cargoes to the vacuole, supporting a function of clathrin in exocytosis. A comparison with lines overexpressing AUXILIN-LIKE1, where inhibition of CME precedes rerouting of secretory cargoes, does not support a homeostatic regulatory mechanism adjusting exocytosis to the rates of endocytosis. Complementary experiments reveal only minor and variably detectable reductions in the rates of CME in secretory mutants, also not indicative of a converse homeostatic mechanism adjusting rates of endocytosis to the rates of secretion.

Hugin+ neurons provide a link between sleep homeostat and circadian clock neurons

Sleep is controlled by homeostatic mechanisms, which drive sleep after wakefulness, and a circadian clock, which confers the 24-h rhythm of sleep. These processes interact with each other to control the timing of sleep in a daily cycle as well as following sleep deprivation. However, the mechanisms by which they interact are poorly understood. We show here that hugin+ neurons, previously identified as neurons that function downstream of the clock to regulate rhythms of locomotor activity, are also targets of the sleep homeostat. Sleep deprivation decreases activity of hugin+ neurons, likely to suppress circadian-driven activity during recovery sleep, and ablation of hugin+ neurons promotes sleep increases generated by activation of the homeostatic sleep locus, the dorsal fan-shaped body (dFB). Also, mutations in peptides produced by the hugin+ locus increase recovery sleep following deprivation. Transsynaptic mapping reveals that hugin+ neurons feed back onto central clock neurons, which also show decreased activity upon sleep loss, in a Hugin peptide–dependent fashion. We propose that hugin+ neurons integrate circadian and sleep signals to modulate circadian circuitry and regulate the timing of sleep.

Evolving interpretable plasticity for spiking networks

Continuous adaptation allows survival in an ever-changing world. Adjustments in the synaptic coupling strength between neurons are essential for this capability, setting us apart from simpler, hard-wired organisms. How these changes can be mathematically described at the phenomenological level, as so-called ‘plasticity rules’, is essential both for understanding biological information processing and for developing cognitively performant artificial systems. We suggest an automated approach for discovering biophysically plausible plasticity rules based on the definition of task families, associated performance measures and biophysical constraints. By evolving compact symbolic expressions, we ensure the discovered plasticity rules are amenable to intuitive understanding, fundamental for successful communication and human-guided generalization. We successfully apply our approach to typical learning scenarios and discover previously unknown mechanisms for learning efficiently from rewards, recover efficient gradient-descent methods for learning from target signals, and uncover various functionally equivalent STDP-like rules with tuned homeostatic mechanisms.

Plant Growth Regulators INCYDE and TD-K Underperform in Cereal Field Trials

Using plant growth regulators to alter cytokinin homeostasis with the aim of enhancing endogenous cytokinin levels has been proposed as a strategy to increase yields in wheat and barley. The plant growth regulators INCYDE and CPPU inhibit the cytokinin degrading enzyme cytokinin oxidase/dehydrogenase (CKX), while TD-K inhibits the process of senescence. We report that the application of these plant growth regulators in wheat and barley field trials failed to enhance yields, or change the components of yields. Analyses of the endogenous cytokinin content showed a high concentration of trans-zeatin (tZ) in both wheat and barley grains at four days after anthesis, and statistically significant, but probably biologically insignificant, increases in cisZ-O-glucoside, along with small decreases in cZ riboside (cZR), dihydro Z (DHZ), and DHZR and DHZOG cytokinins, following INCYDE application to barley at anthesis. We discuss possible reasons for the lack of efficacy of the three plant growth regulators under field conditions and comment on future approaches to manipulating yield in the light of the strong homeostatic mechanisms controlling endogenous cytokinin levels.

Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Objective: The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients.Methods: Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples.Results: We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage.Interpretation: These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

Hierarchy of homeostasis mechanisms of human-machine complexes: problems of their analysis and Implementation

Developing control systems for regional socio-economic and large technical systems is inevitably associated with the concept of human-machine complexes (HMC). They are considered as a set of a large number of hierarchically dependent complex subsystems, including staffs and machines, possessing a certain degree of organization and autonomy, interconnected by mechanisms and means of organization (i.e. material and informational links) to ensure the purposeful functioning of the entire system as a single whole in conditions of tense internal resource close to the limiting ones. The article discusses the hierarchy of interrelated homeostasis mechanisms of the HMC, ensuring both its parameter constancy and the performance of systemic functions at all hierarchy levels. In particular, the following types of homeostasis are considered: a parametric type (the internal circuit of homeostasis), designed to maintain the parameter constancy of HMC active elements and a functional type (the external circuit of homeostasis), ensuring the constancy of its functioning. At the same time, the functional integrity of the system is ensured by the work of the interrelated static-dynamic and entropy-organizational homeostasis mechanisms, which, in turn, in practical activity are implemented through coordination-motivational (CMR), organizational-motivational (OMP) and functional (FMR) mechanisms of regulation. The need for an integrated application of all entropy-organizational regulation mechanisms (CMR, OMR, FMR) in the operators’ activities determines the necessity to use multivariate methods to determine their composition and application. To solve this problem, the article examines the supersystem elements of the activity regulation, which are formed as a result of the operators’ psychological interaction in the process of their activity, as a kind of an abstract system of a higher order, which has its own supersystem properties, its own autonomous metric and conservation laws, and most importantly, its situation reflection which is different from the system one. In this case, homeostatic hierarchical networks, the elements of which are homeostatic mechanisms of HMC operators at various levels, become the basis of HMC structural-hierarchical homeostasis. Thus, being complex systems, HMC synergistically change (adapt) their internal characteristics, thereby ensure the integrity of the entire system functioning, which allows speaking, on the one hand, of their homeostaticity as the HMC most important characteristic, and on the other hand, determining the need to search for new approaches to their methodological description, and, consequently, to organizing their management and design.

The Adipokine Component in the Molecular Regulation of Cancer Cell Survival, Proliferation and Metastasis

A hormonal imbalance may disrupt the rigorously monitored cellular microenvironment by hampering the natural homeostatic mechanisms. The most common example of such hormonal glitch could be seen in obesity where the uprise in adipokine levels is in virtue of the expanding bulk of adipose tissue. Such aberrant endocrine signaling disrupts the regulation of cellular fate, rendering the cells to live in a tumor supportive microenvironment. Previously, it was believed that the adipokines support cancer proliferation and metastasis with no direct involvement in neoplastic transformations and tumorigenesis. However, the recent studies have reported discrete mechanisms that establish the direct involvement of adipokine signaling in tumorigenesis. Moreover, the individual adipokine profile of the patients has never been considered in the prognosis and staging of the disease. Hence, the present manuscript has focused on the reported extensive mechanisms that culminate the basis of poor prognosis and diminished survival rate in obese cancer patients.