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.
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.
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
- 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
- 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
- Heneka, M. T., Golenbock, D. T., and Latz, E. (2015) Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236