A paper published in the journal Science Translational Medicine on October the 9th was quickly jumped on by the press as and hailed as a ‘turning point’ by Prof R Morris at Kings College London. However it is important to note that this study that must be taken with a “pinch of salt” as the earliest prediction of a similar drug for human treatment is 10 years away.
Now for the Science behind the hype:
The proposed cause of the disease has changed many times over the past 15 years, however the current view is that Amyloid-Beta proteins and tau proteins form and accumulate in the brain. This cause a loss of neurons (brain cells), leading to symptoms that are typical to the disease.i
Amyloid-Beta (Aβ) are proteins that are cleaved from the Amyloid Precursor Protein (APP) which is a membrane protein found in neurons. If there is an excess of Aβ proteins in neurons, they oligomerise (group together) to form larger complexes known as plaques. ii
Aβ proteins are the main component of amyloid beta plaques along with others associated with the disease. These plaques contain a protein fold (structural element) which is recognized as abnormal by a pathway called the Unfolded Protein Response (UPR)iii
The UPR stops the production of certain proteins as a defence mechanism to give the cell more time to deal with the problem before resuming its normal protein expression. This pausing of protein synthesis is mediated by the activation of Protein kinase RNA-like ER kinase (PERK).
The activated PERK causes UPR proteins to be expressed and the down-grading of some key proteins including ones needed for synaptic signalling. As the disease progresses, more Aβ proteins accumulate in the brain and cells begin to die in a process known as neurodegeneration.
The recent study in Science Translational Medicine is looking into this pathway in more detail. The compound selected (GSK2606414), produced by GlaxoSmithKline is a selective inhibitor of PERK. If PERK is not active then UPR genes will not be transcribed and normal proteins will be available in the cell.
The papers main claims are:iv
- “GSK2606414 reverses cognitive deficits and prevents clinical disease”
- “GSK2606414 treatment restores synthesis of vital synaptic proteins”
- “GSK2606414 is neuroprotective in mice with prion (misfolded protein) disease”
The paper also pointed out a few issues that need resolving before the drug can be trialled on humans, such as mice suffering weight loss and hyperglycemia due to PERK’s other systemic roles being affected.
This promising work on the Alzheimer’s pathway may lead to a treatment to reduce the symptoms of patients with the disease, and however far away this is, it is really worth researching. I hope that the huge news coverage on this by the press will help kick start the charge towards a treatment and maybe one day a cure.
iiiParker MH, Reitz AB (2000). “Assembly of β-Amyloid Aggregates at the Molecular Level”. Chemtracts-Organic Chemistry13 (1): 51–56.
iv Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, & Mallucci GR (2013). Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Science translational medicine, 5 (206) PMID: 24107777
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