The Transporter

Could ‘retromer' be the key to Alzheimer's treatment?

A key to cellular function — and to life itself — is the movement of proteins and lipids within a cell. As these substances follow their paths, a part of the cell called the endosome acts as the traffic hub, sorting them to be recycled, diverted, secreted or degraded. When the endosome sends them to be recycled back to the cell surface, a complex of proteins plays a role like that of a school crossing guard: it encircles them and helps them on their way. That complex is known as retromer — and its performance may be key to treating Alzheimer's and Parkinson's diseases.

Last spring, in a paper published in Nature Chemical Biology, biochemist Dr. Gregory Petsko revealed a potential new therapeutic approach for these devastating neurodegenerative diseases — one that boosts the function of retromer. In an editorial highlighting the work, noted that the results, while preliminary, have impressed veteran researchers in the Alzheimer's field. As one neurologist told the journal: "The new pro-retromer drug is brilliant."

Dr. Petsko, director of the Helen & Robert Appel Alzheimer's Disease Research Institute and the Arthur J. Mahon Professor of Neuroscience in Weill Cornell's Feil Family Brain and Mind Research Institute, began his work on retromer function a decade ago, not long after retromer was discovered in yeast cells in 1998 and in mammalian cells in 2003. "We were looking for an approach to Alzheimer's research that was different from what other people were doing, an approach that got to something fundamental in the cell," says Dr. Petsko. He found it by collaborating with Dr. Scott Small, a neurologist at Columbia University College of Physicians & Surgeons who in 2004 found that retromer levels were low in the area of the brain where Alzheimer's originates; other collaborators have found that genes active in Alzheimer's disease regulate retromer levels.

Retromer transports amyloid precursor protein. It's a protein thought to be essential for the health of brain cells — but which, when it breaks into fragments, becomes amyloid-beta peptide (or "a-beta"), the substance that clumps into the hallmark plaques of Alzheimer's disease. The researchers hypothesized that when retromer levels are too low or when retromer malfunctions, it allows APP to linger too long in the endosome — an area that's enlarged in the brains of Alzheimer's patients — and there APP encounters the enzyme that begins to break it down. The a-beta plaques are the final fragment of APP's disintegration, and there is some evidence that the intermediate fragments may actually (or also) be what's toxic to the neuron. So Dr. Petsko and his collaborators aimed to find a way to keep APP flowing quickly through the cell by increasing retromer levels. "This was a difficult problem for us experimentally," Dr. Petsko says. "Most therapeutic studies require that you inhibit something, but it's quite another matter to get more of it."

He and his team turned to a strategy they'd pursued, along with the biotechnology company Amicus Therapeutics, for the treatment of Gaucher and Fabry diseases, two genetic, lipid- storage disorders that affect children. By binding a small molecule to an enzyme, they'd increased its stability, thus inducing its levels to rise; drugs based on this work are now in clinical trials. "If you made an origami bird and you wanted to keep it from falling apart, you'd tape one of the seams," Dr. Petsko explains. "The idea would be to use a drug as a kind of molecular tape and hold the protein together more tightly." Dr. Petsko's lab found a site between two of the proteins in the retromer complex into which a drug could fit, interacting with both at the same time. The compound, which acts as what scientists call a "chaperone," stabilized the retromer structure, boosted its overall numbers, and reduced levels of amyloid-beta and other APP misprocessing products in neurons. While it isn't viable as a drug — it is not very stable and would require too-frequent dosing in humans, for one thing — it was proof of concept. "It has shown, I think fairly conclusively, that retromer deficiency is a key issue, and that there is therapeutic promise in fixing that deficiency," Dr. Petsko says. "That tells us a lot more about the nature of the disease — that it isn't just a protein-misfolding disease, but it also involves issues of trafficking in the cell."

The idea that fixing an imbalance in a cell could remove the issue of toxicity is exciting, Dr. Petsko says. Rather than attacking plaques — an approach he likens to traditional thinking about cancer treatment, in which clinicians hit the disease with the equivalent of a nuclear weapon — this approach opens up the possibility for thinking about this disease in a more subtle way. "Philosophically," Dr. Petsko says, "my colleagues and I feel this has real merit."

Dr. Petsko and his collaborators are now researching other conditions that may be affected by retromer levels, including lysosomal storage diseases — such as Sandhoff disease, a rare disorder in which neurons are destroyed — and osteoporosis. Retromer has already been shown to play a role in Parkinson's, and the team is currently seeking to identify the mechanism by which it does so. That effort holds considerable promise for drug discovery, as it's easier to design clinical trials for Parkinson's than Alzheimer's, given that the former is simpler to diagnose and has a well-defined progression. And until scientists determine how to prevent neurodegenerative diseases completely, Dr. Petsko says, the goal is to either stop them in their tracks or turn them into manageable chronic conditions. "Alzheimer's typically progresses over a 10- to 15-year period," he notes. "If it progressed over a 30-year period, it wouldn't be so much of an issue. To really win, we might not have to do much more than change things a little bit."

— Andrea Crawford

This story first appeared in Weill Cornell Medicine,Vol. 14, No. 1.