On the brink of breakthrough


The Kuo Lab begins collaborative research on innovative Alzheimer's disease treatment

Alzheimer’s disease (AD) is often described as a cruel disease because it strips away memories, personality, cognitive functioning and autonomy. Lucinda Willaims, musician and daughter of a person with AD, likens the progressively degenerative neurological disease to many small deaths: "The thing about Alzheimer's is that it's sort of like all these little, small deaths along the way, before they actually physically die."

Globally, an estimated 55 million people are experiencing Alzheimer’s, with an estimated $1 trillion in financial costs associated with the disease. According to the Centers for Disease Control and Prevention (CDC), over 10% of Americans aged 65 and older (6 million people) had AD as of 2022. As the population ages, experts predict the incidence of AD will triple by 2060.

Compounding the medical and financial stressors are the emotional, mental health and socioeconomic burdens on the caregivers, which are often the unpaid spouse and/or adult children of the patient. In the United States, unpaid caregivers spent an estimated 16 billion hours caring for patients with dementia in 2021, valued at $272 billion, according to a study published by the Journal of Managed Care & Specialty Pharmacy.

“There is no real cure or prevention of this devastating disease,” states Min-Hao Kuo, Ph.D., professor in the Michigan State University Department of Biochemistry & Molecular Biology and head of the Kuo Lab at the Michigan State University College of Osteopathic Medicine (MSUCOM) and the College of Natural Science (NatSci). The drugs available to treat AD offer “only modest benefits to the cognitive function of a limited group of patients,” he said. “Innovative approaches are desperately needed.”

This need for innovation is the driving force behind Kuo’s latest research project. He and his research partners are embarking on a joint research project that could lead to a breakthrough in AD treatment.

About the project

Funded by a five-year, $3 million National Institutes of Health (NIH) R01 grant through the National Institute of Neurological Disorders and Stroke (NINDS), Kuo is partnering with a group at the University of Virginia, Charlottesville, led by Cha-Yi (Alex) Kuan, M.D., Ph.D. Together, the labs are looking at treating neurotoxicity and cognitive deficits due to a protein called hyperphosphorylated tau.

Using a new mouse model, the research teams are testing the hypotheses that oligomers of the hyperphosphorylated tau protein cause neurotoxicity that underlies neurodegeneration of patients, and that such damaging effects can be mitigated by the small-molecule compounds apomorphine and raloxifene. These are two prescription drugs found by the Kuo Lab to be potent inhibitors of the toxicity of hyperphosphorylated tau, and have a high potential to be repurposed for clinical treatment of AD.

According to Kuo, the teams are looking at tau in this research project because, “Accumulating evidence demonstrates that the hyperphosphorylated tau protein is likely to be the driver for neuronal death that underlies AD neurodegeneration.”

He said that tau is a protein that associates with microtubules in the axon of neurons, and is generally believed that tau contributes to the stability of microtubules and to the transport of cargos along the axon.

Kuo further explains, “In AD, the tau protein becomes hyperphosphorylated, meaning it contains two to three times higher levels of phosphate groups in each molecule. This chemical modification causes the tau protein to dislodge from microtubules, and to concentrate at the cell body of neurons. These hyperphosphorylated tau molecules then start to form fibrils that eventually grow into neurofibrillary tangles. The appearance of neurofibrillary tangles near the hippocampus correlates with the symptoms of short-term memory loss that signals the early stage of Alzheimer's disease. When the clinical symptoms worsen and progress to affect behaviors and high order cognitive functions, we also see hyperphosphorylated tau spread to the corresponding areas of the brain.”

Forging new paths to behavioral and cognitive research

Up to this point, research into “tauopathy” translational research, as he refers to it, has been scant because of the challenging process of preparing the hyperphosphorylated tau protein with the ability to cause neuronal damages and cognitive deficits in animal models. In other words, it’s been difficult to simulate the damaging effects of the hyperphosphorylated tau protein in clinical trials.

The Kuo Lab’s approach to answering this unmet need is to produce a recombinant hyperphosphorylated tau protein (dubbed “p-tau”) in E. coli, which acts similarly to that in AD patients and has been shown to cause cognitive impairments in animals, including mice and fruit flies.

“A very exciting and potentially groundbreaking discovery is that the behavioral and cognitive deficits, as well as histological abnormalities caused by p-tau, were mitigated by apomorphine, a medication currently used to treat the ‘off’ episodes in Parkinson’s disease patients,” he said. “Apomorphine and raloxifene were found in our pilot screen to be potent protectors against p-tau cytotoxicity and neurotoxicity. The in vivo verification of the potential therapeutic power of apomorphine paves the way for drug repurposing of these two compounds.” Kuo said.

Extending beyond Alzheimer’s disease

The newly funded research project will build on these exciting results to study the AD disease mechanism and drug discovery.

“We hope that the research products from this grant and from our other ongoing projects will give us the momentum for the breakthrough in AD drug development,” Kuo said.

This pioneering hyperphosphorylated tau-based study of Alzheimer’s disease may have far-reaching impacts on other neurodegenerative diseases affected by the protein, including Pick’s disease, progressive supranuclear palsy, frontal lobar degeneration and chronic traumatic encephalopathy. It could also help people with diseases affected by tau aggregates in the peripheral tissues, including Type II diabetes and sporadic inclusion body myositis (sIBM).

“Given the prion-like nature for the progression of tau pathology, it is conceivable many degenerative diseases in the central nervous system and in peripheral share a root of tau abnormalities,” Kuo said. “MSUCOM is at an advantageous position to integrate basic and clinic scientists for translational studies of such diseases. If successful, we will have broad and spectacular impacts that will benefit numerous people.”

Kuo credits his ability to “recruit talented and devoted trainees” (such as graduate students, undergraduate students, and postdocs) and to “foster synergistic collaborations with stellar scientists in academic and industrial sectors” as success factors in landing the grant. “Our gratitude is beyond description,” he said.

He explained the underlying thread between all his research projects is the theme of “living long and happily ever after”— finding ways to prolong the lifespan and developing therapeutics to boost the quality of life and happiness of patients and their loved ones.

Kuo hopes that this groundbreaking research will inspire future researchers. “Rather than trotting on a beaten path, students who are interested in Alzheimer’s research are encouraged to follow the evidence and to keep an open mind to bravely tackle even the most formidable challenge,” he said.


By Elexi Dailey