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Peer-reviewedCC BY-NC-ND 4.0Communications Biology

Temporal and spatial control of phosphatidylinositides using optogenetics ameliorates behavioral deficits in an Alzheimer’s disease mouse model

  • Ana Paula Costa1,2
  • Erica Acquarone3,4
  • Artur Lazarian1
  • Mathieu Herman3
  • Krista M. Wartchow1
  • Nicholas Bartelo5
  • William J. Dartora1
  • Jan Krumsiek5,6
  • Xiang-Ling Li7
  • Jeremy M. Baskin7
  • Ottavio Arancio3,4
  • S. Abid Hussaini3,4,8
1 more authors
  • Laura Beth McIntire1,3,4
8 affiliations
  1. 1Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY USA
  2. 2Present Address: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA
  3. 3Columbia University Irving Medical Center, New York, NY USA
  4. 4Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY USA
  5. 5Department of Systems and Computational Biomedicine, Weill Cornell Medicine, New York, NY USA
  6. 6Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY USA
  7. 7Department of Chemistry & Chemical Biology and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY USA
  8. 8Present Address: Nathan Kline Institute, Orangeburg, NY USA
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Abstract

Deficits in levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] mediate Alzheimer’s disease (AD) pathogenesis and etiology. The depletion of PI(4,5)P2 has been reported in AD in both human brain and animal models. Repletion of the synaptic pool of PI(4,5)P2, through haploinsufficiency of the degrading enzyme, Synaptojanin 1, ameliorated behavioral deficits in a mouse model of AD, in spite of accumulating amyloid. In order to refine the contribution of PI(4,5)P2 to AD, we used optogenetic translocation of the PI(4,5)P2-synthesizing enzyme, phosphoinositide phosphate 4 kinase2A (PIP4K2A) to the plasma membrane using light inducible dimerizable cryptochrome 2 (CRY-2) and the transcription factor CRY2-binding domain (CIBN) fused to the plasma membrane-targeting motif (CAAX). Spatiotemporally controlled production of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] at the plasma membrane induced amelioration of behavioral deficits in a mouse model of AD. Imaging mass spectrometry confirmed alteration of specific PI(4,5)P2 acyl species, di-oleate, indicating that precise PI(4,5)P2 species may ultimately be leveraged for therapeutic intervention.

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Cite

BibTeXRIS
BibTeX
@article{costa2026temporal,
  title = {{Temporal and spatial control of phosphatidylinositides using optogenetics ameliorates behavioral deficits in an Alzheimer’s disease mouse model}},
  author = {Ana Paula Costa and Erica Acquarone and Artur Lazarian and Mathieu Herman and Krista M. Wartchow and Nicholas Bartelo and William J. Dartora and Jan Krumsiek and Xiang-Ling Li and Jeremy M. Baskin and Ottavio Arancio and S. Abid Hussaini and Laura Beth McIntire},
  journal = {Communications Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s42003-026-10517-0},
  url = {https://doi.org/10.1038/s42003-026-10517-0},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Temporal and spatial control of phosphatidylinositides using optogenetics ameliorates behavioral deficits in an Alzheimer’s disease mouse model
AU  - Ana Paula Costa
AU  - Erica Acquarone
AU  - Artur Lazarian
AU  - Mathieu Herman
AU  - Krista M. Wartchow
AU  - Nicholas Bartelo
AU  - William J. Dartora
AU  - Jan Krumsiek
AU  - Xiang-Ling Li
AU  - Jeremy M. Baskin
AU  - Ottavio Arancio
AU  - S. Abid Hussaini
AU  - Laura Beth McIntire
PY  - 2026
DA  - 2026/07/14
JO  - Communications Biology
DO  - 10.1038/s42003-026-10517-0
UR  - https://doi.org/10.1038/s42003-026-10517-0
AB  - Deficits in levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] mediate Alzheimer’s disease (AD) pathogenesis and etiology. The depletion of PI(4,5)P2 has been reported in AD in both human brain and animal models. Repletion of the synaptic pool of PI(4,5)P2, through haploinsufficiency of the degrading enzyme, Synaptojanin 1, ameliorated behavioral deficits in a mouse model of AD, in spite of accumulating amyloid. In order to refine the contribution of PI(4,5)P2 to AD, we used optogenetic translocation of the PI(4,5)P2-synthesizing enzyme, phosphoinositide phosphate 4 kinase2A (PIP4K2A) to the plasma membrane using light inducible dimerizable cryptochrome 2 (CRY-2) and the transcription factor CRY2-binding domain (CIBN) fused to the plasma membrane-targeting motif (CAAX). Spatiotemporally controlled production of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] at the plasma membrane induced amelioration of behavioral deficits in a mouse model of AD. Imaging mass spectrometry confirmed alteration of specific PI(4,5)P2 acyl species, di-oleate, indicating that precise PI(4,5)P2 species may ultimately be leveraged for therapeutic intervention.
SN  - 2399-3642
ER  -