Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells.
Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.


CONCLUSIONS
Several independent studies have implicated tau protein as central to Alzheimer's disease progression and cell-to-cell pathology propagation. In this study, we investigated the ability of different tau species to propagate pathology in human neurons derived from induced pluripotent stem cells, which to date has not been shown. We demonstrated that tau oligomers, but not monomers, induce accumulation of pathological, hyperphosphorylated tau. This effect was accompanied with neurite degeneration, loss of synapses, aberrant calcium homeostasis, imbalanced neurotransmitter release, and ultimately with neuronal death. This study bridges various tau pathological phenotypes into a single and relevant induced pluripotent stem cell neuronal model of human disease that can be applied to the discovery of the mechanisms of tau-induced neurodegeneration.
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486 marija.usenovic@merck.com sophie_parmentier_batteur@merck.com.
Marija
M
Usenovic
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Shahriar
S
Niroomand
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Robert E
RE
Drolet
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Lihang
L
Yao
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Renee C
RC
Gaspar
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Nathan G
NG
Hatcher
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
Joel
J
Schachter
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486.
John J
JJ
Renger
Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486 marija.usenovic@merck.com sophie_parmentier_batteur@merck.com.
Sophie
S
Parmentier-Batteur
D000704:Analysis of Variance; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008297:Male; D044085:Microfluidics; D018625:Microscopy, Atomic Force; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*
D018377:Neurotransmitter Agents; D016875:tau Proteins; D002118:Calcium
Alzheimer's disease; hiPSC neurons; neurodegeneration; pathology propagation; tau oligomer seeds