How Arthritis May Protect Against Alzheimer’s Disease

RA and Amyloid Epidemiological studies have suggested that either rheumatoid arthritis itself – or the anti-inflammatory drugs used to control it – are associated with a reduced risk of developing Alzheimer’s disease. Recent clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) have failed to show a benefit in patients with Alzheimer’s disease and researchers at the University of South Florida have now shown that it may be the disease itself that affords protection.

In a mouse model of Alzheimer’s disease, one of the cytokines that is elevated in patients with rheumatoid arthritis, granulocyte-macrophage colony-stimulating factor (GM-CSF), was shown to improve working memory and learning and to lead to an apparent increase in neural cell connections in the animals’ brains. GM-CSF also led to an accumulation of microglia in the brains of treated animals which was associated with a greater than 50% reduction in β-amyloid peptides. Recombinant human GM-CSF is currently approved to stimulate the production of white blood cells in some cancer patients and the new study, which is published in the Journal of Alzheimer’s Disease, suggests that GM-CSF could also be of benefit to Alzheimer’s patients.

The USF Health Byrd Alzheimer’s Institute plans to begin a pilot clinical trial later this year to investigate recombinant human GM-CSF in patients with mild or moderate Alzheimer’s disease.

First Disease-Modifying Compound Targeting Protein Misfolding

transthyretin crystal structureThe term amyloidosis encompasses a wide variety of diseases characterised by extracellular deposition of insoluble fibrils of abnormally folded proteins in organs and tissues. Transthyretin amyloidosis (ATTR) is a disorder in which a serum protein, transthyretin (TTR), accumulates in tissues such as heart, kidneys, nerves, and intestine. TTR is a 127 amino acid transport protein for thyroxine and retinol which circulates as a tetramer. It is believed that the disease is caused by TTR tetramer dissociation into monomers which misfold and form amyloid deposits. The inherited form of the disease is caused by autosomal dominant mutations in the TTR gene. The only specific treatment at present for this progressive disorder is liver transplantation. TTR is synthesised primarily in the liver and, if an individual receives a new liver, they will no longer produce the mutated version of the protein. Although the procedure has benefitted some patients, for others disease progression continues after the transplant, suggesting that abnormal amyloid deposits may act as seeds, even for normal protein.

Scientists at the Scripps Research Institute investigating new treatments for ATTR have focussed on inhibition of tetramer dissociation, the rate-tafamidis structurelimiting step in amyloid formation, and discovered tafamidis (Fx-1006A), a small molecule that acts as a pharmacological chaperone for TTR and prevents misfolding. The drug stabilizes both wild-type and variant TTR, prevents misfolding of the protein by preventing tetramer dissociation, and inhibits the formation of TTR amyloid fibrils. Tafamidis is being developed by FoldRx Pharmaceuticals who announced last week that the new drug significantly halts disease progression for patients with transthyretin amyloid polyneuropathy (ATTR-PN), a form of ATTR in which the amyloid fibrils are deposited in peripheral nerve tissues. Results from a randomised, controlled Phase II/III clinical study showed that once daily oral treatment with tafamidis was safe and well-tolerated and, compared to placebo, significantly halted disease progression after 18 months (no progression in 60% of tafamidis patients compared with 38% of placebo patients). Placebo-treated patients also experienced a significant deterioration in quality of life compared with tafamidis-treated patients.

Tafamidis is the first disease-modifying compound that targets protein misfolding and it is hoped that it will provide a better alternative to liver transplant for ATTR-PN patients.

Novel Mechanism of γ-Secretase Modulation

It is widely believed that reducing amyloid plaque formation will provide a disease-modifying treatment for Alzheimer’s Disease, either halting or slowing cognitive decline. Amyloid peptides, which aggregate to form neurotoxic plaques, are formed by proteolysis of a precursor protein by the action of two enzymes, β-secretase and γ-secretase. Inhibition of either of these proteases should prevent the formation of amyloid peptides, and much effort has been devoted to the identification of inhibitors. γ-Secretase, particularly, is a promiscuous enzyme and hydrolyses a number of other substrates, including Notch. The Notch signalling pathway is important in many cellular processes and so modulators rather than inhibitors of γ-secretase are preferred.

Amyloid pathway

Relatively early in the search for modulators of γ-secretase, the surprising discovery was made that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, effectively suppress amyloid peptide production while sparing processing of Notch and other γ-secretase substrates. Further studies identified tarenflurbil (R-flurbiprofen, Flurizan, MPC-7869) as a γ-secretase modulator with the potential to treat Alzheimer’s Disease. A recent report in Nature (Kukar et. al., Nature 2008, 453, 925-929) has now shed new light on how such compounds prevent amyloid formation.

tarenflurbil

Using photoprobes, the group were able to show that flurbiprofen does not bind to the γ-secretase protein complex but, instead, binds to the amyloid precursor protein.

Disappointingly, Myriad Genetics have recently discontinued development of Flurizan since it failed in a phase III clinical trial in Alzheimer’s patients.

The study by Kukar et. al. does, however, suggest that it may be possible to identify other small molecules that reduce the formation of amyloid peptides by binding to the precursor protein rather than to the γ-secretase complex. It remains to be seen whether similar ‘substrate-binding’ inhibitors of other proteases can be identified.