The Fisher Fund for Translational Research

The Fund has supported a broad range of research projects investigating neurodegenerative illness from novel angles. With a focus on developing approaches that can contribute to early intervention, this effort has empowered scientists to pursue ambitious ideas and experimental therapeutics in areas where traditional funding is often limited.

The complexity of Alzheimer’s and related neurodegenerative diseases demands a wide spectrum of inquiry—from understanding the molecular and cellular mechanisms that drive disease progression to identifying common biological pathways shared across disease categories.

With support from the Fisher Fund for Translational Research, researchers are exploring the roots of cognitive decline at every level of brain function, including:

• Investigating the mechanisms of neuronal vulnerability and resilience
• Developing tools for early detection and target validation
• Studying pathways involved in memory, inflammation, and neuroprotection
• Mapping shared biochemical features across distinct neurodegenerative disorders

As part of the Fund’s creation, The Rockefeller University’s High Throughput and Spectroscopy Resource Center in 2022 officially became the Fisher Drug Discovery Resource Center, which provides tools and technical expertise for early-stage drug development at the university and beyond.

These initiatives reflect the Fisher Center Foundation’s commitment to innovation and a future where Alzheimer’s and other neurogenerative diseases are nothing but a memory. Thanks to this multidimensional approach, scientists are exploring new avenues for early-stage therapeutic intervention, nurturing the kind of cross-cutting insight that has the potential to turn scientific ideas into hope for millions of people around the world.

Junyue Cao is interested in how the brain changes over a person’s lifetime. To aid this pursuit, he devised a method to track the brain’s progenitor cells, rare cells that differentiate into specialized cell types. Progenitors comprise fewer than one-half percent of brain cells in young individuals. That small proportion drops to a tenth of a percent later in life, reflecting an instability in cell populations that increases with aging. Dr. Cao isolated and analyzed more than 10,000 progenitor cells from multiple sectors of mouse brains spanning three life stages: youth, maturity, and old age.

He learned that as brains age, progenitor cells produce fewer neurons—the cells of thought and memory—and fewer glia, cells that protect and nourish neurons. As these cell types decrease, immune cells that convert to an inflammatory state proliferate. Similar changes were seen in parallel studies of postmortem human brain tissue. Given the roles that inflammation and progressive neuronal loss play in Alzheimer’s disease, the Cao lab’s method shows great promise as a tool to assist in the development and pre-clinical testing of new Alzheimer’s therapeutics.

The efficiency of working memory, or short-term memory, is known to vary from one person to the next. Remarkably, Priya Rajasethupathy and her colleagues have discovered a single gene that may help to explain why. Variations in the gene, named Gpr12, affected the performance of laboratory mice in remembering a simple maze task. The lab team detected strong Gpr12 activity in the thalamus, a brain area not conventionally linked to short-term memory, and mapped coordinating circuits with the hippocampus, a known working memory center. This was the first identification and mapping of a single gene that drives substantial variability in a higher order cognitive process.

Gpr12 is so-named because it encodes a G protein-coupled receptor (GPCR). Importantly, about one-third of all approved drugs target GPCRs. Dr. Rajasethupathy is collaborating with another Rockefeller scientist to solve the structure of the Gpr12 protein, a key step toward identifying small molecule modulators of this receptor that could be developed into drugs for the treatment of memory disorders.

The Alzheimer’s disease drug lecanemab is a focus of interest in the laboratory headed by Sidney Strickland, the Zachary and Elizabeth M. Fisher Professor in Alzheimer’s and Neurodegenerative Disease. Lecanemab blocks the binding of blood-clotting protein fibrinogen to amyloid-beta, the toxic protein that accumulates in the brains of Alzheimer’s patients. By the time lecanemab was approved by the FDA in 2023, Dr. Strickland had already been conducting tests to determine if interactions between amyloid-beta and fibrinogen could be targeted as a potential new treatment for Alzheimer’s disease. This research included a high-throughput screen in the Fisher Drug Discovery Center.

In follow-up investigation with lecanemab, Dr. Strickland and his colleague Erin Norris revealed a previously unknown protective mechanism by which the drug may slow progressive loss of brain function. Their research showed that lecanemab blocks the plasma contact system, which serves as a kind of backup to the body’s primary blood coagulation mechanisms. (They already knew that amyloid-beta is responsible for activating the contact system.) The Strickland lab has developed its own antibody, currently known as 3B, which blocks the contact system by mechanisms other than those seen with lecanemab. In mouse models of Alzheimer’s disease, their test compound inhibited blood vessel occlusion, reduced amyloid deposition in the cerebral cortex, and improved results of behavioral testing. Drs. Strickland and Norris have proposed that an antibody such as 3B may eventually be used in conjunction with lecanemab or similar drugs in Alzheimer’s therapy.

Hermann Steller has proposed an approach to therapy designed to accelerate clearance of damaged proteins from brain cells, a process that becomes less efficient with age and appears to be overwhelmed in Alzheimer’s and Parkinson’s diseases. Cells cannot repair damaged proteins, so they rely on potent clearance mechanisms to remove these products before they can cause harm. In the absence of adequate clearance activity, cellular function deteriorates, and neurons die.

The Steller lab has identified a pathway involving the molecule PI31 as an important participant in the clearance of damaged proteins. Importantly, the research has shown that stimulating the PI31 protein clearance pathway impedes neuronal degeneration and extends lifespan in a mouse model for Parkinson’s disease. Human genetics research has shown that people with a mutation known to impede the activity of PI31 are predisposed to Parkinson’s disease. In addition, mutations in PI31 have been found in patients with Alzheimer’s disease. Dr. Steller’s lab continues to conduct extensive studies of the PI31 pathway in transgenic mouse models and in human biology, with the long-term goal of developing novel medications for Alzheimer’s and other neurodegenerative diseases.