FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model.
basic_science · Level V
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- Record sourced from PubMed, PMID 27834631.
- Also identified by DOI 10.7554/eLife.18691 and PMC identifier 5106215.
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Abstract
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 Aβ<sub>1-42</sub>-induced tau pathology. <i>Fcgr2b</i> knockout or antagonistic FcγRIIb antibody inhibited Aβ<sub>1-42</sub>-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 Aβ<sub>1-42</sub>, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aβ<sub>1-42</sub> increased PtdIns(3,4)P<sub>2</sub> levels from PtdIns(3,4,5)P<sub>3</sub> 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)P<sub>2</sub> metabolism, providing insight into therapeutic potential against AD.
Medical subject headings
- Alzheimer Disease
- Amyloid beta-Peptides
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
- Phosphatidylinositols
- Receptors, IgG
- tau Proteins