Newly awarded research from Michigan State University could result in therapeutic and preventative drugs for Alzheimer’s disease. Dr. Jessica Fortin, assistant professor for the MSU Department of Pathobiology and Diagnostic Investigation, was awarded a Drug Discovery Research Starter Grant by the PhRMA Foundation for her research regarding a protein that may be crux in the battle against Alzheimer’s disease and other neurodegenerative diseases.
Jessica Fortin, BPharm, BSc (chemistry), MSc, DVM, PhD, DACVP, DABT, is a scientific researcher with intense interest—and years of work and study—in protein folding, medicinal chemistry, and neuropathology. Learn more about Dr. Fortin and her research.
In addition to the potential impact of this research, Fortin’s award is notable for other reasons. She is a relatively young scientist, and only just began her faculty position at the MSU College of Veterinary Medicine in fall of 2018. She’s also a woman working in STEM, a growing, but still underrepresented, group.
“Winning this award from the PhRMA Foundation is significant for many reasons. Perhaps most significant is that leaders and innovators from across the pharmaceutical and health care industries have identified Dr. Fortin’s work in biopharmaceutical research to be of high promise for benefiting patient health outcomes,” says Dr. Srinand Sreevatsan, associate dean of Research and Graduate Studies at the MSU College of Veterinary Medicine.
Fortin’s project, “Characterization of new inhibitors of p-tau aggregation and cytotoxicity,” will focus on hyperphosphorylated tau (HPT), the role it plays in the progression of Alzheimer’s disease, and drug candidates that may be able to stop, slow, or prevent Alzheimer’s and other neurodegenerative diseases. The grant is worth $100,000 throughout one year. Drug discovery and drug delivery are new areas of emphasis for the PhRMA Foundation’s awards. Nearly 400 scientists applied for these new funding awards, but only 16 were awarded. Fortin is 1 of those 16.
“When you look at the timeline of Alzheimer’s disease, it’s the formation of the tangles that correlates with the progression of cognitive decline in clinical patients, not the formation of amyloid plaques, as was once commonly thought to be true.”
Previous Alzheimer’s disease research has established that:
Previous drug discovery research did not use clinically relevant hyperphosphorylated tau as a target because a robust way to create and harvest hyperphosphorylated tau isoform proteins in quantities sufficient for research purposes did not exist—until now. HPT has been made available by Fortin's mentor, Dr. Min-Hao Kuo, through a technology that enables hyperphosphorylation. For more information on this work, see:
Many people have heard about amyloid plaques, a popular target in other Alzheimer’s research. When these plaques form, nervous system immune cells, called microglia, move in to clean up the plaques. During this process, tau proteins, which are naturally found in brain cells and help keep brain cells healthy, become hyperphosphorylated. This means all the tau’s phosphorylation sites become saturated with phosphate groups. In healthy humans, each tau protein may have two or three phosphate groups attached. In Alzheimer’s patients, phosphorylation can reach two-to-four times that rate.
HPT is problematic for two reasons: it is sticky and toxic. HPTs clump together and create neurofibrillary tangles. HPT also is toxic to the neurons—cells in the brain responsible for transmitting information throughout the body. According to Fortin, the neurofibrillary tangles and the pathogenesis of Alzheimer’s disease offer important clues regarding the role HPT plays in cognitive decline. “When you look at the timeline of Alzheimer’s disease, it’s the formation of the tangles that correlates with the progression of cognitive decline in clinical patients, not the formation of amyloid plaques, as was once commonly thought to be true,” says Fortin.
Other Alzheimer’s disease researchers already have studied neurofibrillary tangles caused by HPT. However, those researchers did not have access to HPT as a target for drug screening because there was not a robust way to create and harvest HPT isoform proteins in quantities sufficient for research purposes. But thanks to Dr. Min-Hao Kuo, associate professor for the MSU Department of Biochemistry and Molecular Biology and Fortin’s mentor, it is now possible. Using a protein interaction module-assisted function X (PIMAX) system, Kuo was able to create a novel, synthetic HPT. This target, hyper-p-tau, is a more-specific target for drug screening because the tau is hyperphosphorylated at multiple Alzheimer’s disease-relevant sites.
“Hyper-p-tau is a heavily phosphorylated version of tau 1N4R, which is the HPT resembling the HPT found in the brains of Alzheimer’s patients. In essence, Dr. Kuo created a custom, Alzheimer’s disease-specific target—more so than in any previous research,” says Fortin. “Hyper-p-tau is the key to my project.”
Throughout the past decade, drug discovery efforts for Alzheimer’s disease overwhelmingly have focused on anti-amyloid beta therapeutics like amyloid beta-clearing antibodies and beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors. However, most of these therapeutic strategies did not improve cognitive functions of Alzheimer’s patients during Phase III clinical trials.
Of all her small molecules, Fortin’s most promising is JF-19-73.
Fortin's preliminary data indicate that JF-19-73 may be able to bind to a specific and advantageous region of HPT, but more research must be done to explain how this small molecule interacts with HPT to stop aggregation of neurofibrillary tangles.
During her earlier research, Fortin discovered several small molecules, called JF compounds, that prevent hyper-p-tau from sticking together in the first place. Her most potent molecule, JF-19-73, also disrupts hyper-p-tau’s cytotoxic effect in vitro, which suggests it may offer protective benefits to brain cells. Throughout the next year, Fortin will continue testing and refining her JF compounds to optimize them for the inhibition of hyper-p-tau aggregation, as well as screen them for properties that may neutralize HPT’s toxic effects on neurons.
“Our hope is for my small molecule compounds like JF-19-73 to bind to Dr. Kuo’s hyper-p-tau in a way that prevents them from sticking together. This would be a strong indication that the molecules can stop or slow HPT in the brain from forming neurofibrillary tangles and, in doing so, protect neurons from destructive processes that are associated with the formation of neurofibrillary tangles and neurological damage,” says Fortin.
To learn more about Dr. Jessica Fortin’s research, visit the Fortin Drug Discovery Laboratory.
Fortin’s work for this project requires a cross-campus, multi-disciplinary effort with key collaborators: