'Chaperone' Compounds Offer New Approach to Alzheimer's Treatment
Compounds protect neurons from amyloid-beta
Researchers at Columbia University Medical Center, Weill Cornell Medical College, and Brandeis University have come up with a new approach to the treatment of Alzheimer’s disease (AD) involving the so-called retromer protein complex.
Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of AD.
The researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published online in Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Small and his colleagues showed that retromer is deficient in the brains of patients with AD. In cultured neurons, they demonstrated that reducing retromer levels raised amyloid-beta levels, whereas increasing retromer levels had the opposite effect. Three years later, Small showed that reducing retromer had the same effect in animal models, and that these changes led to AD-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
Small and his colleagues wondered whether there was a way to prevent retromer from degrading and to bolster its function.
“Our challenge was to find small molecules — or pharmacologic chaperones — that could bind to retromer’s weak point and stabilize the whole protein complex,” said investigator Dagmar Ringe, PhD.
This was accomplished through computerized virtual screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said lead author Dr. Diego Berman. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of AD.
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said co-senior author Gregory A. Petsko, DPhil. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
Source: Columbia University Medical Center; April 20, 2014.