Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the β-secretase pathway

The link between cholesterol and Alzheimer’s disease has recently been revealed in Niemann Pick type C disease. We found that NPC1-/- cells show decreased expression of APP at the cell surface and increased processing of APP through the β-secretase pathway resulting in increased C99, sAPPβ and intracellular Aβ40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered Aβ/C99 levels in NPC1-/- cells to the levels observed in wt cells. Finding that overexpression of C99, a direct gamma-secretase substrate, does not lead to increased intracellular Aβ levels in NPC1-/- cells vs. CHOwt suggests that the effect on intracellular Aβ upon cholesterol accumulation in NPC1-/- cells is not due to increased APP cleavage by gamma-secretase. Our results indicate that cholesterol may modulate APP processing indirectly by modulating APP expression at the cell surface and, thus, its cleavage by β-secretase

Effects of electric current frequencies, laser irradiation and combined treatment on Saccharomyces cerevisiae viability

In this research, we examined the influence of low voltage (9 V) electric current frequencies (1.4 and 17 Hz), laser irradiation (648 and 532 nm) and combined treatment (one frequency and one laser beam) on the viability of baker’s yeast (Saccharomyces cerevisiae). Each treatment was conducted using modified methods and equipment in air-filter equipped working chamber. Staining was performed by a non-vital/vital staining technique that has shown an increase in viability of all samples. Counting of yeast cells in 1 ml of sample gave us several positive results in terms of different treatments, cell viability and increase in the number of healthy cells. Treatment with electric current at higher frequencies (4 and 17 Hz) showed increased cell death counts and, although compensating by an increase in viability, the 17 Hz frequency was considered more hazardous. The most adequate treatments (both increased viability and cell count) were the combined treatments (1 Hz/4 Hz + one of the two laser beams). Although, all electric treatments show certain increases in cell viability, combined treatments (1 or 4 Hz coupled with green or red laser beam) show the most promise in achieving both increased cell viability and increased cell counts

Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber)

Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat.

The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.This work was supported by a European Research Council grant (grant 294678 Extremeophile Mammal) to G.R.L. E.S.J.S. acknowledges support from the Alexander von Humboldt foundation.This is the final version of the article. It first appeared from Elsevier (Cell Press) via https://doi.org/10.1016/j.celrep.2016.09.03

Rapid molecular evolution of pain insensitivity in multiple African rodents

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.Grants from the European Research Council (advanced grant 294678 to G.R.L.) and the Deutsche Forschungsgemeinschaft SFB 958 (to G.R.L.), by a South African Research Chair for Mammalian Behavioural Ecology and Physiology to N.C.B., and by a National Science Foundation grant to T.J.P.http://www.sciencemag.orghj2019Mammal Research InstituteZoology and Entomolog

Tactile acuity measured on wrinkled and non-wrinkled finger pads.

<p>Wrinkling of the index finger pad skin has no effect on tactile acuity (p = 0.323). Discrimination thresholds (tactile acuity): 1.31±0.06 mm (non-wrinkled fingers, white bar) and 1.39±0.08 mm (wrinkled fingers, black bar). n = 38.</p

The effect of wrinkling on handling dry and submerged objects.

<p>The graphs show the times it took participants to transfer objects from a source container into a target container using only the thumbs and index fingers by passing them through a 5×5 cm transfer hole. (<b>A</b>) In Group 1 (n = 20; height of the transfer hole: 75 cm), there were no differences in handling times for dry or submerged objects with wrinkled (filled circles) and non-wrinkled fingers (empty circles) (wrinkling status: F(1, 16) = 2.572, p = 0.128; object status: F(1, 16) = 3.577, p = 0.077; interaction: F(1, 16) = 0.785, p = 0.389; mean values in pink). (<b>B</b>) In Group 2 (n = 20; height of the transfer hole: 45 cm), no advantageous effect of having wrinkled fingers on handling submerged objects was observed (object status: F(1, 16) = 3.491, p = 0.080). However, participants were slower in handling both dry and submerged objects with wrinkled than with non-wrinkled fingers (wrinkling status: F(1, 16) = 6.476, p = 0.022). Interaction: F(1,16) = 0.076, p = 0.786.</p

Summary of the times taken to transfer dry and submerged objects with either wrinkled or non-wrinkled fingers (Group 1).

<p>In Group 1 (height of the transfer hole: 75 cm), participants transferred dry as well as submerged objects on average equally rapidly with and without wrinkles.</p

Water-Induced Finger Wrinkles Do Not Affect Touch Acuity or Dexterity in Handling Wet Objects

<div><p>Human non-hairy (glabrous) skin of the fingers, palms and soles wrinkles after prolonged exposure to water. Wrinkling is a sympathetic nervous system-dependent process but little is known about the physiology and potential functions of water-induced skin wrinkling. Here we investigated the idea that wrinkling might improve handling of wet objects by measuring the performance of a large cohort of human subjects (n = 40) in a manual dexterity task. We also tested the idea that skin wrinkling has an impact on tactile acuity or vibrotactile sensation using two independent sensory tasks. We found that skin wrinkling did not improve dexterity in handling wet objects nor did it affect any aspect of touch sensitivity measured. Thus water-induced wrinkling appears to have no significant impact on tactile driven performance or dexterity in handling wet or dry objects.</p></div

Summary of the times taken to transfer dry and submerged objects with either wrinkled or non-wrinkled fingers (Group 2).

<p>In Group 2 (height of the transfer hole: 45 cm), participants transferred dry or wet objects equally rapidly but were slower in transferring objects with wrinkled fingers compared to non-wrinkled fingers.</p