FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model.
Amyloid-β (Aβ)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aβ exerts neuropathogenic activity through tau, the mechanistic link between Aβ and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology.Fcgr2bknockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcγRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Aβ1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aβ1-42increased PtdIns(3,4)P2levels from PtdIns(3,4,5)P3to mediate tau hyperphosphorylation. Further, we found that targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we concluded that the FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2metabolism, providing insight into therapeutic potential against AD.
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.|Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Baltimore, United States.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States.
Tae-In
TI
Kam
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.|Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Baltimore, United States.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States.
Hyejin
H
Park
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.
Youngdae
Y
Gwon
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.
Sungmin
S
Song
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.
Seo-Hyun
SH
Kim
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.
Seo Won
SW
Moon
School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
Dong-Gyu
DG
Jo
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea.
Yong-Keun
0000-0002-9686-3120
YK
Jung
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C499172:Fcgr2b protein, mouse; C558298:Mapt protein, mouse; D010716:Phosphatidylinositols; D017452:Receptors, IgG; D016875:tau Proteins; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Alzheimer; E. coli; SHIP2; amyloid; cell biology; fc gamma receptor; human; mouse; neuroscience; phosphoinositide; tau