Attacking Alzheimer’s disease from every angle

The characteristic feature of Alzheimers’s disease is the presence in the brain of two different kinds of abnormal protein structures, the amyloid plaques that are formed from the amyloid beta peptide along the outside of the nerve cells, and the neurofibrillary tangles (NFTs) that are formed by the tau protein inside the nerve cells. As the disease progresses the NFTs become progressively more widespread, leading to nerve cell death, loss of cognitive function and ultimately severe dementia. The Alzheimers Association provides an excellent “brain tour” introduction to the biology of the disease http://www.alz.org/alzheimers_disease_4719.asp.  Unfortunately there are at present few effective treatments available, and while drugs such as Aricept (donepezil) can improve the quality of life of sufferers they appear to have little impact on overall disease progression.  New drugs that can slow down, halt or even reverse disease progression are urgently needed, so the news this week that three drugs which work in different ways have performed well in early clinical trials is very welcome.

The first trial was a Phase II clinical trial of the drug PBT2 in 78 patients suffering from mild to moderate Alzheimer’s disease, and targeted the amyloid plaques that form early in the course of the disease. The trial results showed that those taking PBT2 showed improvements in cognitive function over the duration of the trial when compared to both their own performance at the outset of the trial and that of those taking a placebo. http://esciencenews.com/articles/2008/07/29/alzheimers.disease.patients.show.improvement.trial.new.drug
PBT2 acts by moving zinc and copper ions from outside to inside the nerve cells, and since the amyloid plaques form outside the nerve cells and require zinc and copper ions to form this inhibits the development of the plaques.  The development of PBT2 was greatly assisted by the availability of transgenic mice which have mutations in the gene that encodes the A-beta peptide precursor and develop many of the symptoms of Alzheimer’s disease (1). Using these mouse models of Alzheimer’s disease Dr. Ashley Bush and colleagues at the University of Melbourne and Prana Biotechnology Ltd were able to show that PBT2 was more effective at blocking amyloid plaque formation and cognitive decline than earlier drugs that they had been studying, and these promising results lead to the trial whose results were announced this week.

The second trial targeted the other type of protein aggregate associated with Alzheimer’s disease, the neurofibrillary tangle, and again in a Phase II trial Alzheimer’s disease patients taking drug Rember showed dramatic improvement over those taking a placebo pill http://www.cbc.ca/health/story/2008/07/30/protein-study.html. Rember is a curious drug, it’s actually a chemical called Methylthioninium chloride that has been used medically in the past for a range of conditions, and 20 years ago Professor Claude Wischnik accidently discovered that it could disentangle the bundles of tau proteins in NFTs in vitro. A team of scientists at TauRX Therapeutics Ltd lead by Professor Wischik developed mouse models of Alzheimers to evaluate whether this in vitro observation could translate into a drug that could stop the progression of Alzheimer’s disease  http://www.taurx.com/science_aggregation_hypothesis.aspx

These two trials go some way to finally resolving a debate that has divided the Alzheimer’s disease for decades, namely whether amyloid plaques or NFTs are primarily responsible for causing nerve cell death in Alzheimer’s disease.  Since the mid 1990’s a series of transgenic mouse models of Alzheimer’s disease have been developed, and have taught researchers a lot about how the disease progresses. In particular the transgenic mouse models have demonstrated that while amyloid plaque formation can trigger and accelerate the development of Alzheimer’s disease the formation of NFTs is required for nerve cell death to occur and the full clinical symptoms to be displayed (2).  As a consequence over the past decade many researchers have begun to study treatments that target NFT formation as well as those that target amyloid plaques.  It seems that both sides of the debate were at least half right!

The final trial to report is once again a phase II trail, this time of an anti-inflammatory drug that was approved in Russia a couple of decades ago but has since been superceeded by newer drugs.  In a phase II trial of 183 patients with mild to moderate Alzheimer’s disease  Dimebon was found to improve cognitive ability wwithout causing any serious side effects http://esciencenews.com/articles/2008/07/17/early.study.reveals.promising.alzheimers.disease.treatment.
The team undertaking this work do not yet know how Dimebon combats Alzheimer’s disease, but suspect that it may act by preserving the function of energy producing subcellular organelles called mitochondria and thereby preventing nerve cell death.  The decision to undertake clinical trials of Dimebon in Alzheimer’s disease was prompted  by a study published in 2000 showing that it had neuroprotective properties in a rat model of Alzheimer’s disease  (3).

These three clinical trials all illustrate how important animal research is to the development of treatments for Alzheimer’s disease, by contributing to our understanding of how the disease develops and by providing us with disease models that we can use to evaluate potential treatments.  It’s worth remembering though that these are Phase II trials, and as Tom mentioned in his last post adverse effects are often not identified until the drugs are tested on thousands of patients in Phase III trials. It’s possible, even probable, that not all these drugs will be approved by the FDA and go into clinical use, and if they do it will be in four or five years time. This caveat shouldn’t however diminish our optimism at the end of what has been a very exciting week for Alzheimer’s disease research, for the first time we have clinical trial evidence that Alzheimer’s can be stopped in its tracks.

Cheers
Paul
1) Adlard P.A. et al. “Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta” Neuron. Volume 59(1), Pages 43-55 (2008).

2) McGowan E. et al. “A decade of modeling Alzheimer’s disease in transgenic mice.” Trends Genet. Volume 22(5), pages 281-289 (2006).

3) Lermontova N.N. et al. “Dimebon improves learning in animals with experimental Alzheimer’s disease.” Bull Exp Biol Med. Volume 129(6), Pages 544-546 (2000).

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