In-vivo imaging of pathological protein fibrils in neurodegenerative disorders and a myeloid pathway linking protein depositions and neuronal loss
National Institutes for Quantum and Radiological Science and Technology (Tokio, Japan)
The deposition of misfolded protein species exemplified by aberrant conformers of tau and alpha-synuclein is a pathological hallmark of diverse neurodegenerative disorders. We developed an imaging agent, PBB3, for in-vivo positron emission tomography (PET) visualization of tau pathologies(1) and its derivative, PM-PBB3, enabled high-contrast imaging of tau depositions in patients with diverse tauopathies, including Alzheimer's disease and frontotemporal lobar degeneration syndromes(2). More recently, a new class of PBB3 analogs, the C05 series, has allowed in-vivo optical and PET visualization of alpha-synuclein fibrils in rodent and non-human primate models of disseminating alpha-synuclein pathologies(3) and will be evaluated in humans in FY2021. We also utilized these imaging agents for intravital two-photon laser microscopy to clarify mechanisms linking protein depositions and neuronal death(4). In transgenic mice modeling neurodegenerative tau pathologies, live neurons bearing tau fibrils underwent primary phagocytosis by rod-shaped microglia, followed by transports of vesicles containing neuronal remnants to the brain surface through vertical processes of these microglial cells. Subsequently, dural and subarachnoidal macrophages captured these neuron-derived components and excreted them to subarachnoidal veins as extracellular vesicles. This aggressive elimination of viable neurons led to massive brain atrophy in a progressive manner. Our findings indicate a myeloid pathway composed of rod-shaped microglia and border-associated macrophages responsible for the detrimental removal of living neurons from the brain.
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- Ono et al., bioRxiv doi: 10.1101/2020.10.23.349860.
- Takuwa et al., bioRxiv do: 10.1101/2020.11.04.368977.
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