How understanding cell death could lead to a new drug for Alzheimer’s
Read about a research project we funded into how understanding cell death could lead to a new Alzheimer's drug.
Lead Investigator: Dr Marcus Rattray
Institute: University of Reading
Grant Type: PhD
Grant Amount: £75,000
Start date: 01/10/10
Scientific Title: Preclinical investigation of beta-amyloid mediated astrocyte glutamate transporter dysfunction: proof of concept for novel neuroprotective therapies in Alzheimer's disease
What was the project, and what did the researchers do?
The symptoms of dementia are caused by loss of nerve cells in the brain. Nerve cells must remain in contact with their neighbours in order to stay alive. Specialised cells known as astrocytes are supporting cells in the brain that are needed to allow nerve cells to communicate. Astrocytes rely on certain proteins to do their job properly.
The level of one of these proteins, called EAAT, is greatly reduced in people withAlzheimer's disease. This loss contributes to symptoms of dementia and can cause nerve cell death. The researchers wanted to understand why this protein is reduced and look for possible compounds that that could prevent this reduction or encourage extra production. These compounds could be a basis for a potential drug in the future.
What were the key results, and how will this help in the fight against dementia?
The researchers grew astrocytes in the laboratory and used these to study the EAAT protein in more detail. They found that the reduction of EAAT proteins in the cells occurred when they were exposed to the toxic effects of the key Alzheimer's protein, amyloid.
The researchers then developed a number of methods to test the effect of several drug-like molecules, and found that a number were able to increase the levels of the EAAT protein. They also discovered that stopping the activity of a protein called calpain could prevent the loss of EAAT proteins. In addition, they found that memantine, a treatment already used by some people with Alzheimer's disease, could help to boost levels of EAAT.
Overall, this work has helped further the understanding of the biology behind Alzheimer's disease and has also revealed processes that may be useful for the development of new drugs to treat the condition in the future.
What happened next? Future work and additional grants
The researchers are intending on applying for future grants to continue these lines of investigation once the key data has been published. In particular, the team want to better understand the role of calpain and find out more about whether blocking this enzyme can help protect brain cells.
How were people told about the results? Conferences and Publications
Hoppe JB, Rattray M, Tu H, Salbego CG, Cimarosti H (2013) SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity. Neurosci Lett. 2013 Jun 24;546:51-6.
Tu H & Rattray M. Glutamate transporters and Alzheimer's Disease pathology (review)
Tu H, Hicks D & Rattray M. Beta-amyoid regulation of GLT-1 is dependent on calpain (primary article)
International Society of Neurochemistry meeting, Cancun, Mexico 2013
Joint meeting of the European Society of Neurochemistry & The Biochemical Society, Bath, UK, 2013
Alzheimer's Society conferences 2013, 2012
International Society for Neurochemistry meeting, Athens, 2011
Meeting on glutamate/GABA and neuro-glia-vascular interplay in norm and pathology, Krakow, 2014
Alzheimer's Research UK Yorkshire Regional Network meetings 2013, 2014
Conference poster presentations:
Tu H, Lin H, Peacey E, Grundwald N, Gonzalez T, Rattray M. (2013) The loss of glutamate transporter in astrocyte is dependent on calpain. Journal of Neurochemistry 125 (S1): PSM12-09 Rattray M, Grundwald N, Lin H, Tu H, Gonzalez T, Peacey E. (2011) A cell based ELISA to monitor GLT-1 internalisation and degradation. Journal of Neurochemistry 118 (S1): WE04-18