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

Authors

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

Published in

Communications biology. Jul 14, 2026. Epub Jul 14, 2026.

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.

PMID:
42448968
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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