Todd Golde, M.D., Ph.D.
Alzheimer's Disease
Emory University
Recruited: 2022
As a dual graduate and medical student at the start of his scientific career, Todd Golde contributed to the shaping of an important hypothesis: That a peptide, amyloid beta, caused a protein called tau to accumulate in the brain. This accumulation wreaks the havoc that is Alzheimer’s disease, and the hypothesis gained fame as the Amyloid Cascade Hypothesis.
Today, 30-plus years later, Golde continues to contribute new findings and tools that are relevant to the prevention, diagnosis and treatment of Alzheimer’s. He has become a thought leader in the field, not only because of these contributions, but also for elevating dialogue as to why no cure for Alzheimer’s has yet been found – and advancing the idea that the disease is far more complex than the amyloid-tau-symptoms cascade.
GRA helped recruit Golde to Emory in 2022 from a high-profile position at the University of Florida. There, he led the McKnight Brain Institute, a research enterprise of 200 scientists. The institute is regarded as one of the nation’s most comprehensive and technologically advanced centers for exploring brain and neurological diseases.
Golde holds a long view of Alzheimer’s – he sees the disease as a slow process spanning many decades that leads to brain organ failure. Now that biomarkers associated with the disease have been identified, he expects that, in the near future, screenings will be routine for people at ages long before symptoms typically manifest. These screenings will help identify those at risk, and future interventions could delay or even prevent the onset of symptoms.
This view fits with data from his group that suggests the amyloid peptide is not a direct toxin – but its deposition in the brain leads to the accumulation of other proteins, which then trigger the neurodegenerative phase of the disease. Golde’s current research investigates these accumulated proteins as potential new targets for therapies.
One key contribution Golde made involves using an engineered viral vector, commonly used for gene-based therapeutics, as a tool to speed exploration of Alzheimer’s. The viral vector has already proved effective in growing tangle pathologies – one of the key pathologies in the Alzheimer’s brain – in a petri dish using the brain cells of mice. This viral toolkit is known as rAAV, and using it to engineer a model of Alzheimer’s in days rather than years is a feat akin to adding a rocket engine to a Honda Civic. No other research group is known to have matched Golde’s success in reproducibly growing pathologies in vitro.
Given that rAAV vectors are already used to deliver gene therapies to treat certain diseases, Golde sees the rAAV toolkit as having the potential to do the same for Alzheimer’s. Using the model pathologies created in the lab, Golde believes the rAAV system could also be used to evaluate, and ultimately deliver, biotherapeutics directly to the brain. These would target the myriad pathologies present in the Alzheimer’s brain, including amyloid, tau, neuronal degeneration and inflammation.
This means that each of these preclinical experiments is, in essence, an evaluation of a potential therapy. Using traditional approaches, a lab might be able to test one or two potential therapies a year. By contrast, Golde’s lab can conduct dozens of these experiments a year, greatly increasing the likelihood of success.
While Alzheimer’s is a focal point of Golde’s research, his work extends to other disorders of the brain and neurological system. A particular area of interest is a system of neuroendocrine pathways inside the brain called the HPA axis. Psychological stress activates the HPA axis, eventually triggering the release of cortisol, a steroid hormone that coordinates the repones to stress in the body.
In a 2019 paper in the Journal of Experimental Medicine, Golde and colleagues reported a remarkable finding about the HPA axis. An antibody they created (targeting the apex regulator of the HPA axis) succeeded in suppressing the release of corticosterone in mice, the murine equivalent of cortisol in humans. This suppression meant the response to stress was muted, an event Golde believes can help to fight many different kinds of stress-related disorders in humans.
Industry and academic researchers have attempted to “drug” this pathway with small-molecule therapies in the past. But none of these small-molecule approaches had a lasting impact on cortisol levels, a feature Golde believes is necessary to modify stress-related disorders. In contrast, the antibody developed by Golde’s team suppresses cortisol levels for months after a single dose, and it shows tremendous potential for impacting numerous stress-related disorders including obesity and metabolic disorders, addiction and depression. Even Alzheimer’s disease might be targeted with this antibody – it profoundly impacts the brain in ways that could impact the progression of the disease.
At Emory, Golde leads the Center for Neurodegenerative Disease, a research arm of the Goizueta Institute @ Emory Brain Health. His mission is to expand development of new therapeutics for neurodegenerative diseases and help catalyze research relating to neurodegenerative disease across the campus. Golde recognizes that new approaches are needed, and he hopes the new center and the Goizueta Institute can focus research efforts at Emory and beyond to tangibly improve the lives of those who suffer from these devasting disorders.
Golde is an inventor on over 15 patents and patent applications and is a co-founder of two biotech companies: Lacerta Therapeutics, a gene therapy company, and Andante Biologics, which is commercializing the antibody to fight stress disorders.
Research
- Adeno-associated viral gene therapy
- Alzheimer’s Disease
- Cancer therapeutics
- Dementia
- Immunoproteostasis
- Neurodegenerative diseases
- Neuroimmune interactions in neurodegenerative diseases
- Trigeminal Neuralgia
- Intramembrane cleaving proteases
Straight from the Scholar
“Twenty-five years ago, people didn’t think you could create a Covid antibody and give it to hundreds of thousands of people, especially in the time frame it was done. Technology advances will enable us to produce gene therapies for Alzheimer’s Disease in the future. But we need some technology accelerators, and that’s one area where I’m working to make a contribution.”
