| First Author | Kam TI | Year | 2016 |
| Journal | Elife | Volume | 5 |
| PubMed ID | 27834631 | Mgi Jnum | J:239104 |
| Mgi Id | MGI:5824948 | Doi | 10.7554/eLife.18691 |
| Citation | Kam TI, et al. (2016) FcgammaRIIb-SHIP2 axis links Abeta to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model. Elife 5:e18691 |
| abstractText | Amyloid-beta (Abeta)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Abeta exerts neuropathogenic activity through tau, the mechanistic link between Abeta and tau pathology remains unknown. Here, we showed that the FcgammaRIIb-SHIP2 axis is critical in Abeta1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcgammaRIIb antibody inhibited Abeta1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcgammaRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Abeta1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Abeta1-42 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 FcgammaRIIb-SHIP2 axis links Abeta neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD. |
