Alzheimer’s disease (AD), which accounts for ~60% of senile dementia, is a neurodegenerative disorder marked by fibrillar aggregates of Aβ and tau. However, the underlying toxic species appear to be diffusible aggregates (oligomers) of Aβ and tau, which act as prion-like seeds. A recent breakthrough in AD therapeutics is the FDA approval of Lecanemab, a conformational antibody targeting diffusible Aβ aggregates, the first drug proven to slow down cognitive decline in AD. Regarding therapies against diffusible tau aggregates, our group has collaborated with Aprinoia Therapeutics to develop APNmAb005, a first-in-class immunotherapy which has recently entered phase 1 clinical trial. Our group has made major contributions to the development of APNmAb005 by discovering the therapeutic target (synaptic tau oligomers in AD patients), devising the immunization strategy (oligomers stabilized by vesicle encapsulation), and designing the antibody screening platform (using AD-patient synaptosomes). APNmAb005 specifically recognizes tau oligomers that arise in neurites and become released at synapses. Long-term treatments with APNmAb005 rescues hippocampal neuronal in rTg4510 mice, a highly aggressive tauopathy model. Despite recent advances in oligomer-targeting therapies, many fundamental questions about the structural and biochemical properties of Aβ and tau oligomers remain unresolved. We have recently developed new methods to amplify Aβ oligomers from human AD tissues and identified novel misfolding pathways for tau oligomerization. Additional research into oligomer preparation and characterization will be important for developing next-generation therapies against Aβ and tau oligomers.
Biography
Dr. Hwan-Ching Tai received a B.S. in chemistry from National Taiwan University (2000) and a Ph.D. in chemistry from the California Institute of Technology (2010). His doctoral adviser was Erin Schuman, who currently directs the Max Planck Institute for Brain Research. He conducted postdoctoral research at Harvard Medical School with Bradley Hyman, a renowned leader in tau protein pathology and dementia research.
Dr. Tai started his independent research career in chemical biology as an assistant professor and associate professor at the Department of Chemistry, National Taiwan University. In 2021, he relocated his laboratory to Xiamen University, serving as a Nanchiang Distinguished Professor at the Department of Experimental Medicine, School of Public Health.
Dr. Tai has broad research interests across multiple scientific disciplines, including molecular neurobiology, Alzheimer’s disease mechanisms and therapies, bioanalytical chemistry, multi-omics analyses, cell wall biosynthesis, and lignocellulosic materials. He has made key scientific contributions in three research areas:
(1) Developing a first-in-class therapeutic agent against tau protein oligomers for Alzheimer’s disease treatment.
Dr. Tai was the first to discover the accumulation of toxic tau protein oligomers at the synapses of AD patients (2012). His group collaborated with APRINOIA Therapeutics, a biotech company founded in Taiwan in 2015, to develop APNmAb005, a conformational antibody that recognizes synaptic tau oligomers. APNmAb005 is the world’s first tau-oligomer-targeting therapy to enter phase 1 clinical trial, starting in the US in 2022 (clinicaltrials.gov NCT05344989). Dr. Tai is the first author in the preprint manuscript that describes the preclinical development of APNmAb005 (bioRxiv 2022, doi.org/10.1101/2022.06.24.497452), which has been reported by Alzforum.org (https://www.alzforum.org/therapeutics/apnmab005). Following the clinical approval of Aβ-oligomer- targeting immunotherapy with Lecanemab in 2023, tau-oligomer-targeting immunotherapies have become highly-anticipated candidates for next-generation AD therapeutics.
(2) Solving a century-old puzzle in cell-wall biosynthesis.
Cellulose contained in wood fibers represents nearly 25% of global biomass, making it the most abundant organic material on Earth. Despite being studied for over 100 years, the number of glucan chains in wood cellulose microfibrils remains highly controversial. Dr. Tai developed novel small-angle X-ray scattering and solid-state NMR techniques to uncover the 24-chain core-shell nanostructure of wood cellulose microfibrils, overturning the 36-chain model found in many textbooks (Nature Plants 2023).
(3) Rediscovering the lost secrets of Stradivarius violins.
Why 300-year-old Stradivarius violins produce better tones than modern copies is a profound cultural mystery that puzzled even Albert Einstein. Dr. Tai led an international team involving four synchrotron radiation facilities and dozens of collaborators around the world to investigate precious wood samples removed from Stradivarius violins. They found evidence of secret wood chemical treatments applied by Stradivarius, which led to profound structural and acoustic changes (PNAS 2017 & 2018). Dr. Tai’s findings have been reported by international media outlets including The New York Times, The Washington Post, The Times, The Guardian, BBC, etc.
For his scientific achievements, Dr. Tai has received the Periodic Table of Younger Chemists Award from IUPAC (representing the Phosphorus element), the Changjian Scholar Professorship (China), and the Ta-You Wu Memorial Award (distinguished young scholars of Taiwan, China).
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