Body Wall Muscle Research Articles

Postembryonic development and lifestyle shift in the commensal ribbon worm

BackgroundVarious morphological adaptations are associated with symbiotic relationships between organisms. One such adaptation is seen in the nemertean genus Malacobdella. All species in the genus are commensals of molluscan hosts, attaching to the surface of host mantles with a terminal sucker. Malacobdella possesses several unique characteristics within the order Monostilifera, exhibiting the terminal sucker and the absence of eyes and apical/cerebral organs, which are related to their adaptation to a commensal lifestyle. Nevertheless, the developmental processes that give rise to these morphological characteristics during their transition from free-living larvae to commensal adults remain uncertain.ResultsIn the present study, therefore, we visualized the developmental processes of the internal morphologies during postembryonic larval stages using fluorescent molecular markers. We demonstrated the developmental processes, including the formation of the sucker primordium and the functional sucker. Furthermore, our data revealed that sensory organs, including apical/cerebral organs, formed in embryonic and early postembryonic stages but degenerated in the late postembryonic stage prior to settlement within their host using a terminal sucker.ConclusionsThis study reveals the formation of the terminal sucker through tissue invagination, shedding light on its adhesion mechanism. Sucker muscle development likely originates from body wall muscles. Notably, M. japonica exhibits negative phototaxis despite lacking larval ocelli. This observation suggests a potential role for other sensory mechanisms, such as the apical and cerebral organs identified in the larvae, in facilitating settlement and adhesive behaviors. The loss of sensory organs during larval development might reflect a transition from planktonic feeding to a stable, host-associated lifestyle. This study also emphasizes the need for further studies to explore the phylogenetic relationships within the infraorder Amphiporiina and investigate the postembryonic development of neuromuscular systems in closely related taxa to gain a more comprehensive understanding of ecological adaptations in Nemertea.

Abstract PO1-11-09: Body composition correlates with BMI and menopausal status in patients with breast cancer

Abstract Background: Obesity is associated with higher risk of breast cancer (BC)-related death, all-cause mortality, and recurrence. While used to estimate body fat, body mass index (BMI) is insensitive to body fat distribution and lean muscle mass. We hypothesized that BMI categories (BMI 18.5-24.9 [healthy], 25-29.9 [overweight], and ≥30 kg/m2 [obesity]) would not correlate with CT-derived body composition. Methods: We retrospectively identified 180 patients diagnosed with new or recurrent Stage I-IV BC who presented to Johns Hopkins from 2015-2018 and were part of an institutional database. We extracted demographics, diagnosis date, cancer characteristics, BMI, and CT abdomen pelvis scans from the medical record. Baseline BMI was defined as the closest measurement to diagnosis between 1 year prior and 1 month after diagnosis. Baseline CT was within 6 months of and closest to the baseline BMI date. Fully automated deep-learning algorithms identified L1 and performed muscle and adipose tissue segmentation and quantification. Body composition data included: cross-sectional areas (CSA) of subcutaneous, visceral, and total adipose tissue; the mean, median, and standard deviation of the average of the muscle attenuation (density); and the body wall musculature CSA. ANOVA tests assessed associations between body composition, BMI, and menopausal status. Results: Among 180 patients, 136 (76%) had early-stage BC, and 44 (24%) had metastatic BC. Most patients were women (98%) and non-Hispanic (94%). Patients identified as White (57%), Black (29%), Asian (6%), and Other Race (8%). Sixty percent were post-menopausal. Hormone receptor-positive, HER2-positive, and triple negative subtypes were 56%, 19% and 22%, respectively. At diagnosis, 24% had a healthy BMI while 36% and 41% had overweight and obesity, respectively. All body composition measures were significantly associated with BMI (Table 1). As BMI increased, the average body wall musculature and subcutaneous, visceral, and total adipose tissue CSAs increased while the average muscle attenuation decreased. Specifically, the average visceral adipose tissue CSAs were 2.7 and 4.0-fold larger for overweight and obesity compared to that of the healthy BMI group, respectively, while their average muscle attenuations were 62.4% and 40.6% of the healthy BMI group. Postmenopausal women had 1.5-fold higher visceral adipose tissue CSA and 44.7% less average muscle attenuation compared to premenopausal women. Conclusion: Body composition correlates with all BMI categories in primarily white, non-Hispanic women with breast cancer. As BMI increases, body composition changes reliably, with increased subcutaneous and visceral adipose tissue, increased muscle area, and decreased muscle density. Muscle density, not size/area, is more associated with muscle performance, which can relate to functional status and outcomes. Despite validity concerns, BMI is an accessible and economical surrogate for body adiposity in patients with breast cancer. Postmenopausal status was also associated with greater visceral and total adiposity and lower muscle density. Further investigation is needed to confirm these findings. Table 1: Correlation between body composition, BMI, and menopausal status in patients with breast cancer All measures of body composition were significantly associated with BMI. Visceral adipose tissue increased and muscle density decreased as BMI increased and with post-menopausal status. Citation Format: Terrence Tsou, Tingchang Wang, Amanda Blackford, Ronald Summers, Vered Stearns, Jennifer Sheng. Body composition correlates with BMI and menopausal status in patients with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-09.

Dendrite intercalation between epidermal cells tunes nociceptor sensitivity to mechanical stimuli in Drosophila larvae.

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation.

Recording from Drosophila Larval Body Wall Muscles: Passive Membrane Properties and Basic Features of Synaptic Transmission.

The Drosophila larval body wall muscle preparation was first used for electrophysiological analysis in the 1970s. This preparation has become the "gold standard" for studying neuronal excitability as well as synaptic transmission. Here, we first describe the steps for performing intracellular recording from fly larval body wall muscles and then explain how to record and analyze spontaneous and evoked synaptic potentials. Methods used include larval dissection (filleting), identification of muscle fibers and their innervating nerves, the use of the micromanipulator and microelectrode in penetrating the muscle membrane, and nerve stimulation to evoke synaptic potentials.

Voltage-Clamp Analysis of Synaptic Transmission at the Drosophila Larval Neuromuscular Junction.

Although it is particularly valuable in revealing membrane potential changes, intracellular recording has a number of limitations. Primarily, it does not offer information on the kinetics of membrane currents associated with ion channels or synaptic receptors responsible for the potential change. Furthermore, the resting potential of the Drosophila body wall muscle varies naturally such that the driving force also varies considerably, making it difficult to accurately compare the amplitude of miniature synaptic potentials (minis) or evoked excitatory junction potentials (EJPs). Finally, accurate determination of quantal content based on minis and EJPs is possible only under low-release conditions when nonlinear summation is not a major issue. As the EJP amplitude increases, it creates a "ceiling effect," because the same amount of transmitter will be less effective in depolarizing the membrane when the potential is approaching the reversal potential of glutamate receptors/channels. To overcome these limitations, the voltage-clamp technique can be used, which uses negative feedback mechanisms to keep the cell membrane potential steady at any reasonable set points. In voltage-clamp mode, the amplitude and kinetics of membrane currents can be determined. In the large larval muscle cells of Drosophila, the two-electrode voltage-clamp (TEVC) method is used, in which one electrode monitors the cell membrane potential while the other electrode passes electric currents. This protocol introduces the application of TEVC in analysis of synaptic currents using the larval neuromuscular junction preparation.

Back Cover Image

ON THE BACK COVER: CLIK‐1 (shown in green) is a calponin‐related actin‐binding protein that is predominantly expressed in the body wall muscle of the nematode Caenorhabditis elegans. Overlaps between CLIK‐1 and actin filaments (shown in magenta) generate the whitish green appearance of the sarcomeres.Credit: Shoichiro Ono, Winship Cancer Institute, Emory University School of Medicine image

Distinct developmental patterns in Anopheles stephensi organ systems

Anatomical profiles of insects inform vector biology, comparative development and evolutionary studies with applications in forensics, agriculture and disease control. This study presents a comprehensive, high-resolution developmental profile of Anopheles stephensi, encompassing larval, pupal, and adult stages, obtained through microCT scanning. The results indicate in situ anatomical changes in most organ systems, including the central nervous system, eyes, musculature, alimentary canal, salivary glands, and ovaries, among other organ systems, except for the developing heart. We find significant differences in the mosquito gut, body-wall, and flight muscle development during metamorphosis from other dipterans like Drosophila. Specifically, indirect flight muscle specification and growth can be traced back at least to the 4th instar A. stephensi larvae, as opposed to post-puparial development in other Dipterans like Drosophila and Calliphora. Further, while Drosophila larval body-wall muscles and gut undergo histolysis, changes to these organs during mosquito metamorphosis are less pronounced. These observations, and raw data therein may serve as a reference for studies on the development and the genetics of mosquitoes. Overall, the detailed developmental profile of A. stephensi presented here illuminates the unique anatomy and developmental processes of Culicidae, with important implications for vector biology, disease control, and comparative evolutionary studies.

Analysis of Haemonchus embryos at single cell resolution identifies two eukaryotic elongation factors as intervention target candidates

Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans – a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes’ cellular and molecular biology – which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus – a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.

Islet amyloid polypeptide tagged with green fluorescent protein localises to mitochondria and forms filamentous aggregates in Caenorhabditis elegans

Type 2 diabetes (T2D) is the most common form of diabetes and represents a growing health concern. A characteristic feature of T2D is the aggregation of islet amyloid polypeptide (IAPP), which is thought to be associated with the death of pancreatic β-cells. Inhibiting IAPP aggregation is a promising therapeutic avenue to treat T2D, but the mechanisms of aggregation and toxicity are not yet fully understood. Caenorhabditis elegans is a well-characterised multicellular model organism that has been extensively used to study protein aggregation diseases. In this study, we aimed to develop a simple in vivo model to investigate IAPP aggregation and toxicity based on expression in the C. elegans body wall muscle cells. We show that IAPP tagged with green fluorescent protein (GFP) localises to mitochondria not only in muscle cells but also when expressed in the intestine, in line with previous observations in mouse and human pancreatic β-cells. The IAPP-GFP fusion protein forms solid aggregates, which have a filamentous appearance as seen by electron microscopy. However, the animals expressing IAPP-GFP in the body wall muscle cells do not display a strong motility phenotype, suggesting that the IAPP-GFP aggregates are not considerably toxic. Nevertheless, the mitochondrial localisation and aggregate formation may be useful read-outs to screen for IAPP-solubilizing compounds as a therapeutic strategy for T2D.

Moderate dietary restriction delays the onset of age-associated sarcopenia in Caenorhabditis elegans due to reduced myosin UNC-54 degradation

Sarcopenia, a gradual decrease in skeletal muscle mass and strength, is a major component of frailty in the elderly, with age, (lack of) exercise and diet found to be the major risk factors. The nematode Caenorhabditis elegans is an important model of sarcopenia. Although many studies describe loss of muscle function in ageing C. elegans, surprisingly few report on the loss of muscle mass. Here, in order to quantify loss of muscle mass under various dietary restriction (DR) conditions, we used an internal GFP standard to determine levels of the major body wall muscle myosin (UNC-54) in transgenic unc-54::gfp worms over their lifespan. Myosin density linearly increased during the first week of adulthood and there was no significant effect of DR. In contrast, an exponential decrease in myosin density was seen during the second week of adulthood, with reduced rates of myosin loss for mild and medium DR compared to control. UNC-54 turnover rates, previously determined using pulse-labelling methods, correspond well with the t1/2 value found here for UNC-54-GFP using fluorescence (control t1/2 = 12.0 days), independently validating our approach. These data indicate that sarcopenia is delayed in worms under mild and medium DR due to a reduced rate of myosin UNC-54 degradation, thereby maintaining protein homeostasis.

The development of thoracic and abdominal muscle depends on SDF1 and CXCR4

In vertebrates, the lateral body wall muscle formation is thought to be initiated by direct outgrowth of the dermomyotomes resulting in the elongation of the hypaxial myotomes. This contrasts with the formation of the muscles of the girdle, limbs and intrinsic tongue muscles, which originate from long-range migrating progenitors. Previous work shows that the migration of these progenitors requires CXCR4 which is specifically expressed in the migrating cells, but not in the dermomyotome. Here, we show that cells in the ventrolateral-lip (VLL) of the dermomyotome at the flank level express CXCR4 in a pattern consistent with that of Pax3 and MyoR. In ovo gain-of-function experiments using electroporation of SDF-1 constructs into the VLL resulted in increased expression of c-Met, Pax3 and MyoD. In contrast, a loss-of-function approach by implantation of CXCR4-inhibitor beads into the VLL of the flank region caused a reduction in the expression of these markers. These data show that CXCR4 is expressed in the VLL, and by experimentally manipulating the CXCR4/SDF-1 signaling, we demonstrate the importance of this axis in body wall muscle development.

ERK signaling waves via body-wall muscles guide planarian whole-body regeneration across long distances

Whole-body regeneration is a multifaceted process that reinstates a body to its initial three-dimension size and structure after resection injury. It is well-known that signaling waves such as calcium and extracellular signal-related kinase (ERK) signaling waves can efficiently transmit information between tissues or cells. However, the mechanisms responsible for coordinating wound responses over long distances are largely unexplored. A recent study has reported that the propagation of ERK signaling waves via longitudinal body-wall muscles play an essential role in wound response and whole-body regeneration in planarians, underscoring the significance of feedback interactions between spatially distinct tissues during whole-body regeneration over long distances. These findings not only address the central questions of regenerative biology but also have potential implications for regenerative medicine.

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans.

During aging, proteostasis capacity declines and distinct proteins become unstable and can accumulate as protein aggregates inside and outside of cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of cytoplasmic protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of 3 core protein quality control systems, namely chaperones, the proteasome, and macroautophagy, leads to lower levels of age-dependent protein aggregation in Caenorhabditis elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism that selectively targets newly synthesized proteins to suppress their aggregation and associated proteotoxicity. The safety mechanism relies on macroautophagy-independent lysosomal degradation and involves several previously uncharacterized components of the intracellular pathogen response (IPR). We propose that this protective mechanism engages an anti-aggregation machinery targeting aggregating proteins for lysosomal degradation.

Inhibition of ribosome biogenesis in the epidermis is sufficient to trigger organism-wide growth quiescence independently of nutritional status in C. elegans.

Interorgan communication is crucial for multicellular organismal growth, development, and homeostasis. Cell nonautonomous inhibitory cues, which limit tissue-specific growth alterations, are not well characterized due to cell ablation approach limitations. In this study, we employed the auxin-inducible degradation system in C. elegans to temporally and spatially modulate ribosome biogenesis, through depletion of essential factors (RPOA-2, GRWD-1, or TSR-2). Our findings reveal that embryo-wide inhibition of ribosome biogenesis induces a reversible early larval growth quiescence, distinguished by a unique gene expression signature that is different from starvation or dauer stages. When ribosome biogenesis is inhibited in volumetrically similar tissues, including body wall muscle, epidermis, pharynx, intestine, or germ line, it results in proportionally stunted growth across the organism to different degrees. We show that specifically inhibiting ribosome biogenesis in the epidermis is sufficient to trigger an organism-wide growth quiescence. Epidermis-specific ribosome depletion leads to larval growth quiescence at the L3 stage, reduces organism-wide protein synthesis, and induced cell nonautonomous gene expression alterations. Further molecular analysis reveals overexpression of secreted proteins, suggesting an organism-wide regulatory mechanism. We find that UNC-31, a dense-core vesicle (DCV) pathway component, plays a significant role in epidermal ribosome biogenesis-mediated growth quiescence. Our tissue-specific knockdown experiments reveal that the organism-wide growth quiescence induced by epidermal-specific ribosome biogenesis inhibition is suppressed by reducing unc-31 expression in the epidermis, but not in neurons or body wall muscles. Similarly, IDA-1, a membrane-associated protein of the DCV, is overexpressed, and its knockdown in epidermis suppresses the organism-wide growth quiescence in response to epidermal ribosome biogenesis inhibition. Finally, we observe an overall increase in DCV puncta labeled by IDA-1 when epidermal ribosome biogenesis is inhibited, and these puncta are present in or near epidermal cells. In conclusion, these findings suggest a novel mechanism of nutrition-independent multicellular growth coordination initiated from the epidermis tissue upon ribosome biogenesis inhibition.

Atl (atlastin) regulates mTor signaling and autophagy in Drosophila muscle through alteration of the lysosomal network

ABSTRACT The hereditary spastic paraplegias (HSPs) represent a family of genetic disorders comprising at least 72 different genes with the common pathology of progressive locomotor deficits and spasticity. ATL1/SPG3A (atlastin GTPase 1) encodes an ER fusion protein that controls ER morphology, which implicates ER structure as a causal factor in HSP. Here we use Drosophila to study effects of decreased atl (atlastin) on properties of the larval body wall muscle. We found that muscle atl loss causes accumulation of aggregates containing polyubiquitin (polyUB), mostly bound to the autophagy receptor ref(2)P/SQSTM1/p62. Muscle atl loss also decreased volume and complexity of the endolysosomal network and decreased lysosome number. To determine effects of these lysosomal deficits on progression through the basal autophagy pathway, we expressed Atg8a tagged with both GFP and mCherry in a wild-type and atl mutant background. We found numerous structures containing mCherry but not GFP fluorescence in wild type, indicating that Atg8a was found mostly in mature autolysosomes. In contrast, muscles lacking atl exhibited significant amounts of GFP signal, indicating failure of autophagosome maturation with acidic lysosomes. Many of these GFP-positive puncta contained the late-endosome marker Rab7 but not Lamp1, indicating that some autophagy cargo was accumulating within amphisomes. We also found that this autophagy block was accompanied by an inability to activate the mTor kinase. Our results provide mechanistic insights into the role of atl in maintaining proper function of the autophagy pathway and suggests that certain pathologies in patients with mutations in ATL1/SPG3A might result from altered MTOR signaling. Abbreviations atl atlastin; ALR autophagic lysosome reformation; ER endoplasmic reticulum; GFP green fluorescent protein; HSP hereditary spastic paraplegia; Lamp1 lysosomal associated membrane protein 1 PolyUB polyubiquitin; RFP red fluorescent protein; spin spinster; mTor mechanistic Target of rapamycin; VCP valosin containing protein

Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans.

While spaceflight is becoming more common than before, the hazards spaceflight and space microgravity pose to the human body remain relatively unexplored. Astronauts experience muscle atrophy after spaceflight, but the exact reasons for this and solutions are unknown. Here, we take advantage of the nematode C. elegans to understand the effects of space microgravity on worm body wall muscle. We found that space microgravity induces muscle atrophy in C. elegans from two independent spaceflight missions. As a comparison to spaceflight-induced muscle atrophy, we assessed the effects of acute nutritional deprivation and muscle disuse on C. elegans muscle cells. We found that these two factors also induce muscle atrophy in the nematode. Finally, we identified clp-4, which encodes a calpain protease that promotes muscle atrophy. Mutants of clp-4 suppress starvation-induced muscle atrophy. Such comparative analyses of different factors causing muscle atrophy in C. elegans could provide a way to identify novel genetic factors regulating space microgravity-induced muscle atrophy.

Ultrafast distant wound response is essential for whole-body regeneration

Injury induces systemic responses, but their functions remain elusive. Mechanisms that can rapidly synchronize wound responses through long distances are also mostly unknown. Using planarian flatworms capable of whole-body regeneration, we report that injury induces extracellular signal-regulated kinase (Erk) activity waves to travel at a speed 10-100 times faster than those in other multicellular tissues. This ultrafast propagation requires longitudinal body-wall muscles, elongated cells forming dense parallel tracks running the length of the organism. The morphological properties of muscles allow them to act as superhighways for propagating and disseminating wound signals. Inhibiting Erk propagation prevents tissues distant to the wound from responding and blocks regeneration, which can be rescued by a second injury to distal tissues shortly after the first injury. Our findings provide a mechanism for long-range signal propagation in large, complex tissues to coordinate responses across cell types and highlight the function of feedback between spatially separated tissues during whole-body regeneration.

Muscle in the caterpillar Manduca sexta responds to an immune challenge, but at a cost, suggesting a physiological trade-off.

Although skeletal muscle is a specialized tissue that provides the motor for movement, it also participates in other functions, including the immune response. However, little is known about the effects of this multitasking on muscle. We show that muscle loses some of its capacity while it is participating in the immune response. Caterpillars (Manduca sexta) were exposed to an immune challenge, predator stress or a combination of immune challenge and predator stress. The expression of immune genes (toll-1, domeless, cactus, tube and attacin) increased in body wall muscle after exposure to an immune challenge. Muscle also showed a reduction in the amount of the energy storage molecule glycogen. During an immune challenge, the force of the defensive strike, an important anti-predator behaviour in M. sexta, was reduced. Caterpillars were also less able to defend themselves against a common enemy, the wasp Cotesia congregata, suggesting that the effect on muscle is biologically significant. Our results support the concept of an integrated defence system in which life-threatening events activate organism-wide responses. We suggest that increased mortality from predation is a non-immunological cost of infection in M. sexta. Our study also suggests that one reason non-immunological costs of infection exist is because of the participation of diverse organs, such as muscle, in immunity.

Development and In Vivo Assessment of 4-Phenyltellanyl-7-chloroquinoline-loaded Polymeric Nanocapsules in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common form of dementia in older people, and available treatments are palliative and produce undesirable side effects. The 4-phenyltellanyl-7-chloroquinoline (TQ) is an organochalcogen compound studied due to its pharmacological properties, particularly its antioxidant potential. However, TQ possesses some drawbacks such as low aqueous solubility and high toxicity, thus warranting the search for tools that improve the safety and effectiveness of new compounds. Here, we developed and investigated the biological effects of TQ-loaded polymeric nanocapsules (NCTQ) in an AD model in transgenic Caenorhabditis elegans expressing human Aβ1-42 in their body-wall muscles and Swiss mice injected with Aβ25-35. The NCTQ displayed good physicochemical properties, including nanometer size and maximum encapsulation capacity. The treatment showed low toxicity, reduced Aβ peptide-induced paralysis, and activated an endoplasmic reticulum chaperone in the C. elegans model. The Aβ injection in mice caused memory impairment, which NCTQ mitigated by improving working, long-term, and aversive memory. Additionally, no changes in biochemical markers were evidenced in mice, demonstrating that there was no hepatotoxicity in the tested doses. Altogether, these findings provide insights into the neuroprotective effects of TQ and indicate that NCTQ is a promising candidate for AD treatment.

4-Phenylbutyric acid attenuates amyloid-β proteotoxicity through activation of HSF-1 in an Alzheimer's disease model of the nematode Caenorhabditiselegans

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. The pathogenesis is a complex process, in which the proteotoxicity of amyloid-β (Aβ) was identified as a major factor. 4-Phenylbutyric acid (4-PBA) is an aromatic short-chain fatty acid that may attenuate Aβ proteotoxicity through its already shown properties as a chemical chaperone or by inhibition of histone deacetylases (HDACs).In the present study, we investigated the molecular effects of 4-PBA on Aβ proteotoxicity using the nematode Caenorhabditis elegans as a model. Computer-based analysis of motility was used as a measure of Aβ proteotoxicity in the transgenic strain GMC101, expressing human Aβ1-42 in body wall muscle cells. Aβ aggregation was quantified using the fluorescent probe NIAD-4 to correlate the effects of 4-PBA on motility with the amount of the proteotoxic protein. Furthermore, these approaches were supplemented by gene regulation via RNA interference (RNAi) to identify molecular targets of 4-PBA.4-PBA improved the motility of GMC101 nematodes and reduced Aβ aggregation significantly. Knockdown of hsf-1, encoding an ortholog essential for the cytosolic heat shock response, prevented the increase in motility and decrease in Aβ aggregation by 4-PBA incubation. RNAi for hda-1, encoding an ortholog of histone deacetylase 2, also increased motility. Double RNAi for hsf-1 and hda-1 revealed a dominant effect of hsf-1 RNAi. Moreover, 4-PBA failed to further increase motility under hda-1 RNAi.Accordingly, the results suggest that 4-PBA attenuates Aβ proteotoxicity in an AD-model of C. elegans through activation of HSF-1 via inhibition of HDA-1.