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<p>Deficits in levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P<sub>2</sub>] mediate Alzheimer’s disease (AD) pathogenesis and etiology. The depletion of PI(4,5)P<sub>2</sub> has been reported in AD in both human brain and animal models. Repletion of the synaptic pool of PI(4,5)P<sub>2</sub>, 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)P<sub>2</sub> to AD, we used optogenetic translocation of the PI(4,5)P<sub>2</sub>-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)P<sub>2</sub>] 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)P<sub>2</sub> acyl species, di-oleate, indicating that precise PI(4,5)P<sub>2</sub> species may ultimately be leveraged for therapeutic intervention.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Ana Paula Costa,
  • Erica Acquarone,
  • Artur Lazarian,
  • Mathieu Herman,
  • Krista M. Wartchow,
  • Nicholas Bartelo,
  • William J. Dartora,
  • Jan Krumsiek,
  • Xiang-Ling Li,
  • Jeremy M. Baskin,
  • Ottavio Arancio,
  • S. Abid Hussaini,
  • Laura Beth McIntire

摘要

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.