Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Exploring a "Nature-Inspired" Strategy for Enhancing the Pharmacology of Small Molecules: Towards the Development of Next Generation Anti-Infectives.

HIV is now a pandemic of staggering proportions. Unfortunately, the current generation of antiretroviral therapeutics is only partially and temporarily effective in suppressing viral replication due to rapid metabolism leading to liver toxicity, resistance, and poor pharmacokinetics. Thus, there is a burgeoning need to develop innovative approaches for prolonging the lifetimes of these drugs. Here, we propose a novel and potentially general methodology for enhancing the stability of HIV-1 protease inhibitors and other small molecules. This strategy emerged from our interest in understanding the unusual pharmacology behind the natural product FK506, a compound that is an excellent substrate for metabolic P450 enzymes in vitro, yet has an unexpectedly long half-life in humans (t½ ~40 hours). This apparent contradiction may partially be explained by the observation that FK506 is predominantly sequestered into the cytosol of peripheral blood cells. Both erythrocytes and leukocytes are a rich source of FKBP, yet little metabolism occurs here as these cells do not express significant levels of P450 enzymes. Therefore, we hypothesized that FKBP binding compounds, such as FK506, might be protected from exposure to metabolic enzymes by partitioning into this protected cellular niche. During my thesis research, we tested this model by designing and synthesizing a series of bifunctional, FKBP-binding small molecules and evaluating their pharmacokinetic properties in vitro and in vivo. These efforts led to the discovery of SLFavir, an FKBP-binding antiviral with nanomolar potency against HIV-1 protease. We determined that SLFavir is sequestered into the cytosol of erythrocytes and that its lifetime in mice is improved by >20-fold. Furthermore, we observed that binding to FKBP partially blocks its interactions with the CYP3A4 P450 isozyme, making it less susceptible to degradation. Finally, to enable modular synthesis of additional bifunctional compounds, we developed a chemical platform using microwave-assisted olefin cross metathesis to rapidly append FK506 to other drugs, including the antibiotics ampicillin and ciprofloxacin. The key discovery made during my thesis research is that covalently tethering FKBP-binding groups to existing drugs dramatically improves their persistence via cellular partitioning. We expect this “nature-inspired” strategy to yield antivirals and other small molecules with exciting new pharmacokinetic profiles.Ph.D.Molecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/84508/1/pmarinec_1.pd

Pilot study of an English language coaching opportunity for volunteering among US military Veterans with depression, anxiety, and/or post-traumatic stress disorder

Background: Many military Veterans experience mood and anxiety disorders and might benefit from purposeful social interactions. In this pilot study, we evaluated a program in which Veterans with these disorders provided coaching via webcam for English-language learners (ELLs). Methods: Veterans with depression, anxiety, and/or PTSD and ELLs were recruited online. Pairs participated in up to 8 videoconferencing sessions. Pre-post measures of Veterans’ mental health included the PHQ-8, GAD-7, PCL-5, and a scale of “mattering.” Volunteers and ELLs completed satisfaction surveys, and ELLs reported their comfort and fluency with English. Results: Veterans (N = 26) were on average 49.6 years old (SD: 15.2), 57.7 % were men, and 53.9 % reported that they often experienced a lack of companionship or social isolation. Pairs completed on average 6.2 sessions. Satisfaction in both groups was high, and 73.1 % of participants said that they planned to keep in touch. Mean scores improved for Veterans’ symptoms of depression (from 10.6 to 7.6, P=.0001), anxiety (from 9.0 to 6.5, P=.001), and PTSD (from 29.2 to 22.8, P=.0007). The proportion of Veterans with at least moderate symptoms improved for depression (61.5 % to 38.5 %; P=.014) and anxiety (38.5 % to 19.2 %; P=.025). Mattering scores improved (P=.008). ELLs reported improvements in their English comfort and fluency. Limitations: This was an uncontrolled pilot trial with short-term outcomes designed primarily to evaluate the feasibility of the intervention rather than test hypotheses about effect sizes. Conclusions: This intervention may represent a scalable opportunity for Veterans to increase positive socialization and reduce symptoms of depression, anxiety, and PTSD

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden.

BackgroundIt has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.ResultsHere, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.ConclusionsNeuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted