20 Sep Amyloid Targeting Therapy More Likely To Be Effective Early in Alzheimer’s Disease
MedicalResearch.com Interview with:
Dr Christina Elliott PhD
Department of Old Age Psychiatry
King’s College London
MedicalResearch.com: What is the background for this study?
Response: Amyloid-beta (Aβ) and its precursor protein, APP have been long implicated in pathogenesis of Alzheimer’s Disease but how they contribute to disease is not fully understood. This has been further compounded by numerous failed clinical trials which attempted to target Aβ therapeutically.
In Alzheimer’s Disease there is an overproduction of Aβ, which can disrupt how neurons communicate at structures called synapses. It is thought that progressive synapse loss underpins cognitive impairments commonly seen in Alzheimer Disease patients such as memory loss.
Our previous work highlighted a central role of the signalling pathway Wnt signalling in Aβ mediated synapse loss through the induction of dickkopf-1 (Dkk1), a well-known modulator of Wnt signalling.
The aim of this study was to further investigate the molecular mechanisms of Aβ mediated synapse loss and explore whether this is connected to the overproduction of Aβ. By dissecting out the key signalling events involved we hoped this would allow us to identify drugs which could be putative therapeutics for Alzheimer’ Disease.
MedicalResearch.com: What are the main findings?
Response: In our most recent paper we report three major findings:
- Characterisation of a novel function of the amyloid precursor protein (APP) as a Wnt signalling modulator, directly linking synapse loss and amyloid overproduction.
- The discovery of a feedback loop where synapse loss drives amyloid production, which in turn can drive further destruction of neuronal connections and disease progression.
- These phenomena can be blocked by fasudil, a drug already in clinical use in China and Japan for other diseases.
MedicalResearch.com: What should readers take away from your report?
Response: There are three main take-home messages/recommendations arising from our study:
- The function of APP and its role in Alzheimer’s Disease extends far beyond simply being the source of Aβ.
- Clinical intervention particularly with amyloid targeting therapies is more likely to be effective early in the Alzheimer’s disease course.
- By identifying key molecules and signalling pathways underpinning Alzheimer’s Disease pathogenesis we may be able to identify drugs already in the clinic which may be repurposed. Ultimately this may help speed up the identification of drugs that may help treat this intractable disease.
Christina Elliott, Ana I. Rojo, Elena Ribe, Martin Broadstock, Weiming Xia, Peter Morin, Mikhail Semenov, George Baillie, Antonio Cuadrado, Raya Al-Shawi, Clive G. Ballard, Paul Simons & Richard Killick
Translational Psychiatry volume 8, Article number: 179 (2018
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