Salsalate, long used for rheumatoid arthritis, reduces toxic tau protein in mice study
A chemical relative of aspirin is potentially useful in treating a neurodegenerative illness like Alzheimer’s disease and possibly Alzheimer’s itself, according to a study by California scientists.
In a mouse model of frontotemporal dementia, giving salsalate reversed memory loss and protected the hippocampus, a part of the brain essential for memory formation. The drug appears to work by reducing toxic buildup of tau, a protein also implicated in Alzheimer’s.
Most Alzheimer’s research has focused on tau’s more famous cousin, beta amyloid, long the prime suspect in Alzheimer’s. Both are abnormal forms of normal proteins. When altered, they become toxic and damage neurons, leading to their death. Several drugs targeting beta amyloid have reached the clinic, but none to date have been proven effective.
Salsalate is now being tested in several clinical trials, including one for another tau-related neurological disease, progressive supranuclear palsy, or PSP.
Meanwhile, no drugs targeting tau are available for Alzheimer’s, say researchers led by scientists from the Gladstone Institutes at UC San Francisco.
The study was published Monday in Nature Medicine. It is available online at j.mp/alzsalsalate.
Salsalate inhibits a process called acetylation, which makes tau more toxic, the study found.
“One of the main enzymes that acetylates tau is p300, which can be inhibited by salicylate or SSA, an ancient drug commonly used as an NSAID,” the study stated.
“Pharmacokinetically, SSA is quickly metabolized into its active component, salicylate. Unlike salicylate, aspirin (acetylsalicylate) leads to higher levels of ac-tau in cultured neurons. SSA and aspirin have been widely used to treat rheumatoid arthritis and related illnesses in the past decades, and work presumably via inhibition of cyclo-oxygenase (COX). Interestingly, patients taking NSAIDs, including salicylate and derivatives, have a reduced risk of AD.”
Trials with more specific inhibitors of COX didn’t find a protective effect against Alzheimer’s, the study noted. That could be explained if the protective effect is actually due to inhibiting p300.
“Targeting tau acetylation could be a new therapeutic strategy against human tauopathies, like Alzheimer’s disease and FTD,” said Dr. Eric Verdin, a co-senior author, in a press release. “Given that salsalate is a prescription drug with a long-history of a reasonable safety profile, we believe it can have immediate clinical implications.”
However, Dr. Paul Aisen, director of the University of Southern California’s San Diego-based Alzheimer’s Therapeutic Research Institute, said it is unlikely that the approach will succeed.
“Interesting but very preliminary,” Aisen said by email. “In my view, the likelihood that salsalate will prove to be an effective therapy for AD or other tauopathies is small. It is misleading to say that this work has ‘immediate clinical implications.’ ”
Aisen is a proponent of the theory that beta amyloid is the main driver of Alzheimer’s. He is leading a study funded by Eli Lilly & Co. that uses an experimental Lilly drug to reduce amyloid accumulation in people with signs of amyloid buildup, but who have no Alzheimer’s symptoms.
Aisen led the study at UC San Diego, but after he left for USC in June, Lilly transferred its funding to follow him. Another component remains at UC San Diego.
Like Aisen, Dave Schubert, a Salk Institute scientist researching Alzheimer’s drugs, said the study’s conclusions went beyond the evidence given.
“My impression is that it is an interesting study, but likely with overstated conclusions with regard to therapy and even mechanism,” Schubert said by email.
“The claim in the press release ‘We identified for the first time a pharmacological approach that reverses all aspects of tau toxicity,’ can not be true because in the mouse model and humans nerve cells die, and unless salsalate induces the production of new nerve cells to replace the old ones, there is now way to ‘reverse’ the pathology.”
Schubert said the study didn’t show that the acetylated tau hypothesized to harm neurons is concentrated in human neurons or synapses. Moreover, there are safety concerns about using salsalate against Alzheimer’s.
“While salsalate has been used for years as an anti-inflammatory, it is quite toxic at high doses over extended periods of time as would be required for a chronic disease like AD,” he wrote. “Also, as the authors point out, there are a lot of other potential targets for salsalate that could account for the animal data.
“As with all drug candidates, the only way to find out if they have any therapeutic value it to get them into people with the disease in a clinical trial.”
The salsalate study was funded by the Tau Consortium and the National Institutes of Health.