A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination

Qing Bai, Enhua Shao, Denglei Ma, Binxuan Jiao, Seth D. Scheetz, Karen A. Hartnett-Scott, Vladimir A. Ilin, Elias Aizenman, Julia Kofler and Edward A. Burton ()
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Qing Bai: University of Pittsburgh
Enhua Shao: University of Pittsburgh
Denglei Ma: University of Pittsburgh
Binxuan Jiao: University of Pittsburgh
Seth D. Scheetz: University of Pittsburgh
Karen A. Hartnett-Scott: University of Pittsburgh
Vladimir A. Ilin: University of Pittsburgh
Elias Aizenman: University of Pittsburgh
Julia Kofler: University of Pittsburgh
Edward A. Burton: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/− mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.

Date: 2024
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DOI: 10.1038/s41467-024-52173-0

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