#sharetheorange


The Alzheimer’s Research UK (ARUK) conference 2016 took place in Manchester on the 8th and 9th of March. Researchers mostly from the UK, but also guest speakers from Germany and the US, presented their research that covered different fields of study related to Alzheimer’s disease (AD). However, the conference for the author of this blog already started the day before with the PhD day. This day was just for PhD students working on AD or AD related topics and gave them the opportunity to present their work in a more informal environment. The students presented their results in the form of posters or presentations and to the blog author’s delight also negative (or less “good looking”) results were presented which promoted vibrant discussion. Tea and lunch breaks were used to browse posters which pushed PhD students to get in touch with each other. The day was completed by presentations of academic and industrial representatives that gave insight into different career paths.

Lucas.png

Figure 1 | Sussex PhD students who participated in the conference. From left to right: Mahmoud, Karen, Saskia, Devkee, Lucas, Rebecca, Joanne and Luca.

With the PhD day already being a great success, the following days were sure to turn out to be as good. While more basic AD-related concepts and research were covered during the first day, the second day provided talks about new treatment approaches for dementia, as well as AD drug discovery and development. Two talks were in particular interesting:

Evidence is pointing towards inflammation processes that may trigger and influence AD pathology. One inflammation factor that seems involved and is activated in AD is the NLRP3 inflammasome (1). The NLRP3 inflammasome is a multiprotein complex which is formed inside macrophages and microglial cells and that catalyses the activation of caspase-1. Caspase-1 in return converts interleukin-1β (IL-1β) into its active form which is secreted and triggers an immune response. Most commonly, nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of inflammatory conditions that act through inhibition of cyclooxygenase 1 and/or 2. Dr David Brough and colleagues at the University of Manchester hypothesized that NSAIDs may supress inflammation through a mechanism dependent on NLRP3 inflammasome inhibition and thus could potentially be repurposed as inflammasome inhibitors. Screening identified fenamates (fenamic acid, mefenamic acid) to be able to block NLRP3 formation by inhibition of the volume-regulated anion channel (VRAC). Other NSAIDs such as ibuprofen or diclofenac did not show any effect on NLRP3 mediated inflammation. Nevertheless, the other NSAIDs may still exert a positive effect via alternative pathways. Prof Michael Heneka from the University of Bonn (Germany), who gave a talk on targeting innate immunity in AD, demonstrated that these NSAIDs are great activators of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR-γ was shown in transgenic APP/PS1 mice to increase Aβ removal by microglial cells (2). The activating effect of NSAIDs on PPAR- γ may also explain their efficacy in reducing the risk of AD (3). Conclusively, NSAIDs may be an interesting class of anti-inflammatory drugs that could be repurposed in the treatment and/or prevention of AD.

lucas2

Figure 2 | Activation of the NLRP3 inflammasome and production of active IL-1β. Activation of microglial cells via the Toll-like receptor (TLR) or cytokine receptors induces the production of components of the NLRP3 inflammasome, as well as pro-IL-1β. Lysosomal damage by Aβ leads to assembly and activation of the inflammasome that in turn activates caspase-1. Caspase-1 processes pro-IL-1β to its bioactive form which is released. Picture from (3)

The second talk that strongly caught the interest of the author of this blog was the introduction of the Alzheimer’s Research UK Drug Discovery Alliance – a coordinated initiative between the ARUK, Oxford University, Cambridge University and University College London that aims to accelerate the identification for new treatment for AD and other forms of dementia. The Drug Discovery Alliance is especially interested in new and unexplored biological targets and in doing so is keen to hear from researchers across the research community about potential proteins, enzymes or pathways that play a role in AD. By combining the individual strengths of all the three university institutes, the alliance hopes to drive innovation in dementia drug discovery.

 

Blog writted by: Lucas Kraft

 

References

  1.            Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., and Golenbock, D. T. (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 493, 674–678
  2.            Mandrekar-Colucci, S., Karlo, J. C., and Landreth, G. E. (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J. Neurosci. 32, 10117–28
  3.            Heneka, M. T., Golenbock, D. T., and Latz, E. (2015) Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236

Drug discovery- a child’s play


Last Sunday I took my, almost 10 year old, daughter to our  first ever visit to the Brighton Science Festival.

The decision to go came after finding out that PhD students from the Sussex Drug Discovery Centre (SDDC), where having a workshop aiming to introduce children from 7 to 14 to the concept of drug discovery.

We arrive at Hove Park School, a secondary school in Hove where the event was taking place, around lunch time. We were hoping that arriving in the middle of meal time, the place would be less crowded, but we found out that families were still eager to visit the exhibitions with empty stomachs. As  soon as we arrived we headed to the class room where the SDDC where having their display, but we did not even attempt to wait in the queue. It seemed that our PhD students were attracting lots of attention, and later found out that the Saturday queues were even longer. So we went around the school and visited other stands. Navigating around the school was not easy, lots of confusing corridors, staircases and rooms with little or poor indication. On our third attempt to get into the room where the Drug Discovery  demonstration was taking place, we decided to wait in the 15min queue. Once in the queue kids received a lab coat, a pair of goggles a pen and a little notebook. Kids were getting excited even before starting their tour around the room.

Fifteen minutes later the group moved into the first stall where the children were received by James; James is a PhD student in Biochemistry and despite on his second day at the fair, and having countlessly repeated the same words James was enthusiastically talking about proteins. He had prepared an experiment to show how proteins work by demonstrating how a piece of liver (full of proteins) would destroy a H2O2 (a “nasty chemical” according to what kids would remember after the show)… and with a bit of liquid soap in the mixture the kids were screaming of excitement watching a big lump of foam expanding in a measuring cylinder.

Next was Katie’s turn to helps kids design a new drug!! Katie is doing her PhD in Chemical Biology also at the SDDC. The group of kids were given a chemistry model kit and a piece of paper, representing a bacteria’s protein, with a big white section, representing the pocket where the ligand binds. The children were given total freedom to attempt to create a molecule that could fit in the white pocket. Some of the designs were quite imaginative; while most of the kids tried to fit the pocket with a flat molecule, some other very creative kids went beyond that and build a 3D structure…we might see them working at the SDDC in the future!!  Once the kids had finished designing their drugs, they had to test whether their models would fit into the bacteria’s protein pocket made of papier mâché, and also check that it would not fit into a similar protein found in humans. What a clever way of explaining to kids what side effects of drugs are.

SDDCBrighton

Tom and Hayley, both Chemistry PhD students at the University of Sussex, had the kids doing a real chemistry experiment!! Wasn’t that fun!! The intention of the demonstration was not to know which chemicals were being mixed and which reaction was taking place, but that by adding one chemical to the another a chemical reaction could occur. The PhD students had carefully planned the reaction by choosing one that would form a yellow precipitate when adding one colourless solution to another colourless one, resulting in even more screams of excitement when the yellow powder appeared inthe kids’ Erlenmeyer flasks. It was then demonstrated the purification method of re-crystallisation, which was performed by the demonstrators as it involved heating up the reaction flasks. Nevertheless, the children were carefully following up the discussion on how a chemical dissolves at high temperatures and precipitates again when cooled down.

Last but not least, Lucas, also a Biologist PhD student at the SDDC, went on to explain about biochemical assays. In kids’ words, if the drug they had made was good or not. This was again a hands on experiment where they added a solution of the drug into a solution of the protein, followed by the addition of the “detection reagent”. If the solution turned pink, Eureka!! the drug was doing its job.
Overall, the kids had a great time at the SDDC workshop, they had a chance to do some real experiments and they were even dressed up as proper scientists!! A success!!

I am sure next year the SDDC PhD students will be asked to repeat the job, however, I am also sure those involved will ask for a few more pair of hands. It was full-time non-stop two day job with no time for breaks in order to satisfy the eager of the little ones to discover the world of “Making Marvellous Medicines”.

Blog written by Carol Villalonga-Barber