His team searches beyond the hallmark Alzheimer’s disease proteins for alternative treatments

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In his laboratory at the USF Health Byrd Alzheimer’s Center, neuroscientist David Kang, PhD, focuses on how different types of proteins damage the brain when they accumulate there. In the case of Alzheimer’s disease, decades of good science has zeroed in on amyloid and tau, as the two types of hallmark proteins driving the disease process that ultimately kills brain cells.

Dr. Kang and his team investigate molecular pathways leading to the formation large, sticky amyloid plaques between brain cells, and to the tau neurofibrillary tangles inside brain cells –including the interplay between the two proteins. But, he is quick to point out that amyloid and tau are “not the full story” in the quest to understand how normally aging brains go bad.

“Our goal is to understand as much of the entire Alzheimer’s disease process as possible and then target specific molecules that are either overactive or underactive, which is part of the drug discovery program we’re working on,” said Dr. Kang, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Neuroscientist David Kang, PhD, (third from left)  stands with his team in his laboratory at the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Attacking dementia from different angles 

Dr. Kang’s group takes a multifaceted approach to studying the biological brain changes that impair thinking and memory in people with Alzheimer’s, the most common type of dementia, as well as Lewy body, vascular and frontotemporal dementias.

That includes examining how damaged mitochondria, the energy-producing power plants of the cell, contribute to pathology in all neurodegenerative diseases. “Sick mitochondria leak a lot of toxins that do widespread damage to neurons and other cells,” Dr. Kang said.

Dr. Kang’s team was the first to identify how mutations of a gene, called CHCHD10, which contributes to both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), cause both mitochondrial dysfunction and protein pathology called TDP-43. Their findings on the newly identified mitochondrial link to both neurodegenerative diseases were published in Nature Communications in 2017.

The role of selective degradation in ridding cells of abnormal proteins, old or damaged organelles (including mitochondria) and other debris is another key line of research pursued by Dr. Kang and colleagues.

A single stained nerve cell | Microscopic image courtesy of Kang lab

“We believe something more fundamental is going wrong in the brain during the aging process to tip the balance toward Alzheimer’s disease – beyond what we call proteinopathy” or deposits of malformed proteins like toxic amyloid and tau, said Dr. Kang, whose work is bolstered by nearly $8 million in grant funding from the National Institutes of Health (NIH), the Veterans Administration (VA merit awards) and the Florida Department of Health.

“I think one of the fundamental things happening is that the (cellular) plumbing system isn’t working to clear out all the accumulating junk,” he said. “That’s why we’re looking at the protective clearance mechanisms (autophagy and mitophagy) that would normally quickly remove misfolded proteins and dysfunctional mitochondria.”

Unfortunately, pharmaceutical trials to date have yielded no effective treatments for Alzheimer’s disease, the sixth leading cause of death in the U.S.  Most clinical studies have centered on developing medications to block or destroy the amyloid protein plaque formation, and a few have targeted the tau-containing neurofibrillary tangles. The five Alzheimer’s drugs currently available may provide temporary relief of symptoms, such as memory loss and confusion. But, they do not prevent or delay the mind-robbing disease as toxic proteins continue to build up and dismantle the brain’s communication network.

Lesson learned: The critical importance of intervening earlier

Some scientists argue that the “amyloid hypothesis” approach is not working. Dr. Kang is among those who maintain that amyloid plays a key role in initiating the disease process that leads to brain atrophy in Alzheimer’s – but that amyloid accumulation happens very early, as much as 10 to 20 years before people experience memory problems or other signs of dementia.

Early detection and treatment are key, Dr. Kang says, because as protein plaques and other lesions continue to accumulate in the brain, reversing the damage may not be possible.

“One reason we’ve been disappointed in the clinical trials is because so far they have primarily targeted patients who are already symptomatic,” Dr. Kang said. “Over the last decade we’ve learned that by the time someone is diagnosed with early Alzheimer’s disease, or even mild cognitive impairment, the brain has degenerated a lot. And once those nerve cells are gone they do not, for the most part, regenerate… The amyloid cascade has run its course.”

As protein plaques and other lesions continue to accumulate, becoming apparent with MRI imaging, reversing the damage may not be possible.  So, for anti-amyloid therapies – or even those targeting downstream tau – to work, patients at risk of Alzheimer’s need to be identified and treated very early, Dr. Kang said.

USF Health is recruiting healthy older adults with no signs of memory problems for a few prevention trials. A pair of Generation Program studies will test the effectiveness of investigational anti-Alzheimer’s drugs on those at high genetic risk for the disease before symptoms start. And, the NIH-sponsored Preventing Alzheimer’s with Cognitive Training (PACT) study is examining whether a specific type of computerized brain training can reduce the risk of mild cognitive impairment and dementias like Alzheimer’s disease in those age 65 and older.

To accelerate early intervention initiatives, more definitive tests are needed to pinpoint biomarkers that will predict Alzheimer’s disease development in genetically susceptible people. Dr. Kang is hopeful about the prospects.  His own team investigates how exosomes, in particular the lipid vesicles that shuttle proteins and other molecules from the brain into the circulating bloodstream, might be isolated and used to detect people at risk of proteinopathy.

“I think within the next five years, some type of diagnostic blood test will be available that can accurately identify people with early Alzheimer’s brain pathology, but not yet experiencing symptoms,” he said.

Graduate research assistant Yan Yan, a member of Dr. Kang’s research team, works at a cell culture hood.

Searching for alternative treatment targets

Meanwhile, Dr. Kang’s laboratory continues searching for other treatment targets in addition to amyloid and tau — including the enzyme SSH1, which regulates the internal infrastructure of nerve cells, called the actin cytoskeleton. SSHI, also known as slingshot, is needed for amyloid activation of cofilin, a protein identified by the USF Health neuroscientists in a recent study published in Communications Biology as a possible early culprit in the tauopathy process.

“Cofilin is overactive in the brains of Alzheimer’s patients so if we can inhibit cofilin by targeting slingshot, it may lead to a promising treatment,” Dr. Kang said.

Ultimately, as with other complex chronic diseases, Alzheimer’s may not be eliminated by a single silver-bullet cure.  Rather, Dr. Kang said, a combination of approaches will likely be needed to successfully combat the neurodegenerative disorder, which afflicts 5.8 million Americans.

“I think prevention through healthy living is definitely key, because brain aging is modifiable based on things like your diet as well as physical activity and brain exercises,” he said.  “Also, we need to focus on earlier diagnosis, before people become symptomatic, and develop next-generation drugs that can attack the disease on multiple fronts.”

Xingyu Zhao, PhD, a research associate in the Department of Molecular Medicine, is among the scientists in Dr. Kang’s laboratory studying the basic biology of the aging brain.

Fascinated by how the brain works — and malfunctions

Dr. Kang came to USF Health in 2012 after nearly 20 years as a brain researcher at the University of California San Diego, where he earned M.S. and PhD degrees in neurosciences and completed NIH National Research Service Award fellowships in the neuroplasticity of aging.

As an undergraduate Dr. Kang switched from studying engineering to a dual major in science/psychology. He began focusing on neurosciences in graduate school, he said, because tackling how the brain works and malfunctions was fascinating and always challenged him.

“With every small step forward, we learn something else about the basic biology of the aging brain,” said Dr. Kang, “It’s not just helpful in discovering what therapeutic approaches may work best against Alzheimer’s disease – we’re also learning more about other neurodegenerative conditions affecting the brain.”

In addition to leading day-to-day research operations at the Byrd Center and helping to recruit new Alzheimer’s investigators, Dr. Kang holds the Mary and Louis Fleming Endowed Chair in Alzheimer’s Research and serves as a research neurobiologist at the James A. Haley Veterans Haley Veterans’ Hospital.

He has authored more than 50 peer-reviewed journal articles on brain aging and Alzheimer’s disease research. A member of the NIH Clinical Neuroscience and Neurodegeneration Study Section since 2016, he has served on multiple national and international editorial boards, scientific panels and advisory boards.

Dr. Kang sits next to a computer monitor depicting stained microscopic images — a single neuron (far left) and the two hallmark pathological proteins for Alzheimer’s disease, tau tangles (center) and amyloid plaques (right).

Some things you may not know about Dr. Kang

• His parents were Presbyterian missionaries in Africa, so he spent nine years of his early life (third through 10^th grade) in Nigeria.
• Dr. Kang practices intermittent fasting, often forgoing breakfast and eating only within an 8-hour window. Animal studies indicate the practice may contribute to lifespan and brain health by improving cellular repair through the process of autophagy, he said. “Autophagy really kicks your cells’ plumbing system into gear to clear out all the waste.”

-Video and photos by Allison Long, USF Health Communications and Marketing