Dr. Sonia Koyama is a researcher at the Tokyo Metropolitan Institute of Gerontology (TMIG), a premier Japanese research institution dedicated to understanding the biology of aging and neurodegenerative diseases. Her research focuses on the molecular mechanisms of tau aggregation and propagation in 4R-tauopathies, with particular emphasis on post-translational modifications, tau strain diversity, and the development of cellular and iPSC models of PSP and corticobasal degeneration (CBD).
Dr. Koyama's work has established a comprehensive understanding of how 4R-tau forms the pathological aggregates that define PSP and CBD:
- Aggregation kinetics: Studies have characterized the nucleation, elongation, and branching phases of 4R-tau filament formation, identifying critical kinetic parameters that distinguish PSP from AD tau aggregation
- Post-translational modifications (PTMs): Comprehensive mapping of tau PTMs in PSP brain tissue has revealed that specific patterns of phosphorylation, acetylation, and truncation characterize 4R-tau pathology. The 2020 study established that acetylation at Lys280 blocks proteolytic cleavage and stabilizes toxic tau conformers
- Co-factors and seeding: Research has identified that polyamines, metals (Zn2+, Cu2+), and RNA molecules accelerate 4R-tau nucleation, providing mechanistic insight into the self-replicating nature of tau pathology
Dr. Koyama pioneered the development of patient-derived iPSC models for PSP and CBD:
- TMIG cohort: The 2016 derivation paper established protocols for generating neurons and glia from PSP patients carrying MAPT mutations (P301S, IVS5+10) and sporadic cases. These neurons recapitulate key features: 4R-tau accumulation, reduced mitochondrial function, and increased susceptibility to oxidative stress
- 2024 breakthrough: A landmark study using TMIG iPSC models identified genetic and chemical modifiers of tau propagation, screening 3,000+ compounds for tau propagation inhibitors and identifying HDAC6 as a high-value target
- 2025 extension: Single-cell transcriptomics of iPSC-derived neurons revealed cell-type-specific vulnerability patterns — certain neuronal subtypes accumulate tau faster and show earlier transcriptional dysregulation, providing a cellular substrate for understanding PSP clinical heterogeneity
¶ Tau Propagation and Spreading
A central theme of Dr. Koyama's research is understanding how tau pathology spreads through neural circuits:
- Cell-to-cell transmission: Using microfluidic chambers and co-culture systems, her lab has characterized the mechanisms of tau release (synaptic vesicles, exosomes, free diffusion) and uptake (LDLR-family receptors, macropinocytosis)
- Vulnerability factors: Studies have identified that synaptic activity, neuronal activity state, and glial cells all modulate the efficiency of interneuronal tau transfer[@koyama2024propagation]
- Prion-like properties: Early work established the seeded nature of PSP tau aggregates — patient-derived tau fibrils efficiently templated the conversion of wild-type tau into pathological conformations in cellular and animal models
Dr. Koyama has been at the forefront of characterizing distinct tau strains in different 4R-tauopathies:
- 2025 strain study: Using cryo-EM and biochemical profiling, her group demonstrated that PSP and CBD produce structurally distinct tau filament conformations that maintain their identity upon serial passage — analogous to prion strains. These strain differences explain the distinct clinical-pathological phenotypes
- Diagnostic implications: The strain concept has practical applications — seed amplification assays (RT-QuIC, PMCA) show differential detection efficiency for PSP vs CBD seeds, suggesting that assay optimization for specific strains could improve diagnostic accuracy
An underappreciated aspect of PSP is the prominent oligodendroglial tau pathology. Dr. Koyama's work has illuminated this:
- 4R-tau in oligodendrocytes: Oligodendrocytes in PSP accumulate 4R-tau in globular inclusions (often called "coiled bodies"), and her work has characterized the cellular mechanisms — including MBP phosphorylation changes, myelin lipid composition shifts, and transport deficits
- Contribution to disease: Studies suggest that oligodendrocyte tau pathology contributes to white matter damage, demyelination, and axonal degeneration in PSP, independent of neuronal tau burden
- Therapeutic targeting: Since oligodendrocytes are post-mitotic and difficult to target with small molecules, her work has explored gene therapy approaches and remyelination-promoting strategies
Dr. Koyama contributes to both fluid and imaging biomarker research:
- Tau PET correlations: A 2024 clinicopathological study correlated ante-mortem tau PET (MK-6240) binding with postmortem tau burden, validating the specificity of tau PET for 4R-tauopathies and identifying regional SUVR thresholds for diagnostic use
- Fluid biomarkers: Comparative studies of CSF and plasma tau forms (total tau, p-tau181, p-tau217, p-tau231) have established that each marker provides complementary information — p-tau231 being most specific for PSP, while NfL tracks progression
- PTM-based biomarkers: Her PTM mapping work has informed the development of assay-agnostic ELISA platforms that detect specific tau modifications as disease state markers
Imaging-pathology correlations have been a consistent thread in her work:
- Regional specificity: MRI cortical thinning patterns in PSP correlate with regional tau burden in a topographically specific manner — midbrain atrophy predicts substantia nigra tau load, cerebellar dentate nucleus atrophy predicts oligodendroglial tau
- Subtype associations: Different PSP clinical variants show distinct atrophy patterns that reflect the preferential involvement of specific neuronal populations and circuits
Early in her career, Dr. Koyama investigated the intersection of metabolic dysfunction and tau pathology:
- AGEs in PSP: Advanced glycation end products (AGEs) accumulate in PSP tau inclusions, suggesting that metabolic dysfunction contributes to tau aggregation kinetics through cross-linking and oxidative stress
- Mitochondrial dysfunction: Studies have shown that PSP neurons exhibit reduced mitochondrial mass, altered dynamics (fission/fusion imbalance), and impaired respiration — creating a feedforward loop where tau pathology drives mitochondrial damage, which accelerates tau aggregation
The Tokyo Metropolitan Institute of Gerontology (TMIG) is one of Japan's leading research centers on aging and neurodegeneration. Dr. Koyama's work at TMIG benefits from:
- State-of-the-art iPSC facility for generating patient-derived cell lines
- Collaboration with the Tokyo Metropolitan Neurological Hospital for clinical sample access
- Linkage to the Japanese Brain Bank Network (Japan Brain Bank Consortium)
- Access to tau PET imaging through partnerships with Japanese university hospitals
- International collaborations with groups in the US (UCSF, Mayo Clinic), Europe (UCL, University of Munich), and Asia-Pacific
- MAPT genetics group: Ongoing work on MAPT mutation carriers from Japanese cohorts, linking genotype to molecular phenotype
- Tau PET consortium: Multi-site study validating tau PET in 4R tauopathies across Asian populations
- iPSC neuroscreening: Collaboration with RIKEN BSI on high-content compound screening
- Prion research community: Interactions with prion biologists informing tau strain characterization
- Single-cell transcriptomics of PSP brain reveals cell-type specific tau vulnerability patterns (Nat. Neurosci., 2025)
- Distinct tau strain signatures in PSP and CBD (Sci. Transl. Med., 2025)
- Tau propagation in cellular and animal models of PSP (Acta Neuropathol., 2025)
- Mechanisms of tau aggregation in 4R tauopathies (Acta Neuropathol., 2024)
- Human iPSC 4R tauopathy models reveal modifiers of tau propagation (Acta Neuropathol., 2024)
- Tau PET correlates with postmortem tau burden in 4R tauopathies (Ann. Neurol., 2024)
- Post-translational modifications of tau in PSP (Brain, 2023)
- Oligodendrocyte tau pathology in 4R tauopathies (J. Neuropathol. Exp. Neurol., 2023)
- CSF and plasma tau biomarkers in 4R tauopathies (Alzheimer's Dement., 2023)
- Tau isoform composition in PSP subtypes (Acta Neuropathol. Commun., 2022)
- MRI correlates of tau pathology in PSP (Neurology, 2022)
- Tau seed amplification assay performance in 4R tauopathies (Mov. Disord., 2021)
- Acetylation and phosphorylation of tau in PSP (J. Biol. Chem., 2020)
- Cellular models of tau propagation in 4R tauopathies (Neurobiol. Dis., 2019)
- Comprehensive mapping of tau PTMs in PSP brain (Acta Neuropathol., 2018)
- Mechanisms of tau spread in PSP (J. Neurosci., 2017)
- Derivation of tauopathy patient iPSCs (Stem Cell Rep., 2016)
- AGEs in tau pathology (Neurobiol. Aging, 2016)
- Prion-like properties of PSP tau aggregates (PNAS, 2015)