Brain Neprilysin Activity and Susceptibility to Transgene-Induced Alzheimer Amyloids

Neprilysin (NEP) is a zinc metalloproteinase that degrades enkephalins, endothelins, and the Alzheimer’s disease amyloid ß (Aß) peptides. NEP-deficient mice possess increased levels of brain Aß1-40 and Aß1-42. The objective of this study was to determine whether tissue NEP specific activity differs according to age and/or across mouse strains, especially those strains predisposed toward formation of Aß-amyloid plaques following overexpression of the human Alzheimer amyloid precursor protein (APP). The C57Bl/6J mouse strain appears to be relatively susceptible to cerebral amyloidosis, whereas the Swiss Webster (SW) strain appears more resistant. We investigated whether NEP specific activity in brain and kidney homogenates from SW and C57 mice of 6, 40, and 80 weeks old varied according to mouse strain, age, and gender. Among the variables tested, NEP specific activity varied most dramatically across mouse strain, with the kidney and brain of SW mice displaying the highest activities. Aging was associated with a reduction in brain NEP specific activity in both trains. Gender-specific differences were identified in kidney but not in brain. We conclude that aging- and strain-dependent ifferences in NEP specific activity may play a role in the differential susceptibility of some mouse strains for developing cerebral amyloidosis following human APP overexpression

Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1

<p>Abstract</p> <p>Background</p> <p>Generation of the amyloid β (Aβ) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid β precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-<it>trans</it>-Golgi network (<it>TGN</it>) sorting and generation of APP derivatives, including Aβ at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-<it>TGN </it>sorting of APP and its derivatives.</p> <p>Results</p> <p>Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and Aβ.</p> <p>Conclusion</p> <p>These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and Aβ by PKC and ROCK2.</p

Psychedelics as potential catalysts of scientific creativity and insight

Creativity, that is the creation of ideas or objects considered both novel and valuable, is among the most important and highly valued of human traits, and a fundamental aspect of the sciences. Dreams and hypnagogic states have been highly influential in promoting scientific creativity and insight, contributing to some important scientific breakthroughs. Phenomenologically, the latter states of consciousness share a great deal of overlap with the psychedelic state, which has also been associated with facilitating scientific creativity on occasion. The current article proposes that the dream, hypnagogic and psychedelic states share common features that make them conducive to supporting some aspects of scientific creativity and examines the putative underlying neurophenomenological and cognitive processes involved. In addition, some notable occurrences of scientific insights that have emerged from these types of altered states are reviewed and shared common features are presented, providing a ground for future research. The psychedelic state may have its own characteristic features making it amenable to creativity enhancement, such as brain hyperconnectivity, meta-cognitive awareness, access to a more dependable and sustained altered state experience, and potential for eliciting sustained shifts in trait openness. The contextual factors which may contribute to enhancement of scientific creativity and insight will be evaluated. While research in this area is limited, further work to elucidate how psychedelics may best contribute to scientific creativity enhancement is warranted

Psychological variables implied in the therapeutic effect of ayahuasca: A contextual approach

Ayahuasca is a psychedelic decoction originating from Amazonia. The ayahuasca-induced introspective experience has been shown to have potential benefits in the treatment of several pathologies, to protect mental health and to improve neuropsychological functions and creativity, and boost mindfulness. The underlying psychological processes related to the use of ayahuasca in a psychotherapeutic context are not yet well described in the scientific literature, but there is some evidence to suggest that psychological variables described in psychotherapies could be useful in explaining the therapeutic effects of the brew. In this study we explore the link between ayahuasca use and Decentering, Values and Self, comparing subjects without experience of ayahuasca (n = 41) with subjects with experience (n = 81). Results confirm that ayahuasca users scored higher than non-users in Decentering and Positive self, but not in Valued living, Life fulfillment, Self in social relations, Self in close relations and General self. Scores in Decentering were higher in the more experienced subjects (more than 15 occasions) than in those with less experience (less than 15 occasions). Our results show that psychological process variables may explain the outcomes in ayahuasca psychotherapy. The introduction of these variables is warranted in future ayahuasca therapeutic studie

Breaking Up (Amyloid) Is Hard to Do

Gandy and Heppner discuss the implications of a new animal study on our understanding of the pathogenesis and treatment of Alzheimer disease

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness

Background: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. Aims: The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. Methods: We conducted a combined reanalysis of five independent datasets ( N = 3817). Using standard and regularized regression analyses, we tested the relationship between degree of experience with various psychedelic substances (binary and continuous) and NR, both within a subsample of psychedelic-experienced participants as well as the complete sample including psychedelic-naïve participants. Results/Outcomes: Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Salvia divinorum, ketamine, and ibogaine) was a reliable predictor of NR and its subdimensions. Weaker, less reliable results were obtained for the pharmacologically similar N,N-dimethyltryptamine (DMT). Results replicate when including psychedelic-naïve participants. In addition, among people exclusively experience with psilocybin, use frequency positively predicted NR. Conclusions/Interpretation: Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectations/use settings are responsible for this observation

Transpersonal ecodelia: surveying psychedelically induced biophilia

Objective: To explore the perceived influence of psychedelic experiences on participants’ relationship with the natural world. Method: A total of 272 participants reporting previous use of psychedelics completed free-text response requests via an online survey. Thematic analysis was used to explore group participant responses. Results: Participants who described a pre-existing relationship with nature reported that psychedelics acted to re-establish and bolster their connection to nature. Those reporting no previously established connection to nature described psychedelics as helping them bond with the natural world. Underlying both of these were reports of transpersonal experiences, of which ‘interconnectedness’ was most frequently linked to shifts in attitudes and behaviours. Participants were also asked to reflect on previous psychedelic experiences that took place in nature and reported a range of benefits of the natural setting. Conclusions: These findings suggest that psychedelics have the capacity to elicit a connection with nature that is passionate and protective, even among those who were not previously nature oriented. More research is needed to explore the potential implications of psychedelic use outside laboratory-controlled settings in order to enhance these important effects

Dystonia Type 6 Gene Product Thap1: Identification Of a 50 kDa DNA-binding Species In Neuronal Nuclear Fractions

Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50–52 kDa in vitro and in vivo, and verified the previously identified species at 29–30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6

The potential synergistic effects between psychedelic administration and nature contact for the improvement of mental health

Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics