FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model
Tae-In Kam,
Hyejin Park,
Youngdae Gwon,
Sungmin Song,
Seo-Hyun Kim,
Seo Won Moon,
Dong-Gyu Jo,
Yong-Keun Jung
Affiliations
Tae-In 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 Park
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
Youngdae Gwon
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea
Sungmin Song
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea
Seo-Hyun Kim
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea
Seo Won Moon
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, Korea
Dong-Gyu Jo
School of Pharmacy, Sungkyunkwan University, Suwon, Korea
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. Fcgr2b knockout 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 Aβ1-42 increased PtdIns(3,4)P2 levels from PtdIns(3,4,5)P3 to 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)P2 metabolism, providing insight into therapeutic potential against AD.
