| First Author | Han X | Year | 2022 |
| Journal | EBioMedicine | Volume | 78 |
| Pages | 103980 | PubMed ID | 35367771 |
| Mgi Jnum | J:323105 | Mgi Id | MGI:7260408 |
| Doi | 10.1016/j.ebiom.2022.103980 | Citation | Han X, et al. (2022) KIBRA regulates amyloid beta metabolism by controlling extracellular vesicles secretion. EBioMedicine 78:103980 |
| abstractText | BACKGROUND: Previous research has revealed that KIBRA controls secretion of extracellular vesicles (EVs) by inhibiting the proteasomal degradation of Rab27a and EVs play an important role in amyloid beta (Abeta) metabolism and transmission during Alzheimer's disease (AD) pathogenesis. Here, we further test the hypothesis that KIBRA regulates Abeta metabolism via the endosomal-lysosomal system. METHODS: We generated KIBRA knockout mice on a 5XFAD background and KIBRA knockdown cells in murine HT22 cells with stably overexpressing APP. Various forms of Abeta and quantification of EVs were analyzed by biochemical methods and nanoparticle tracking analysis, respectively. Multivesicular bodies (MVBs) were visualized by electron microscopy and confocal fluorescent microscopy. In a population-based cohort (n = 1419), KIBRA genotypes and plasma Abeta levels were analyzed using multiple-PCR amplification and Simoa, respectively. FINDINGS: Multiple forms of Abeta were dramatically attenuated in KIBRA knockout mouse brain, including monomers, oligomers, and extracellular deposition, but KIBRA knockout had no effect on intraneuronal APP C-terminal fragment beta (APP-CTFbeta)/Abeta levels. KIBRA depletion also decreased APP-CTFbeta/Abeta-associated EVs secretion and subsequently enhanced MVBs number. Furthermore, we found that excessive accumulation of MVBs harboring APP-CTFbeta/Abeta promoted the MVBs-lysosome fusion for degradation and inhibition of lysosomal function rescued secretion of APP-CTFbeta/Abeta-associated EVs. More importantly, whole exon sequencing of KIBRA in a large population-based cohort identified the association of KIBRA rs28421695 polymorphism with plasma Abeta levels. INTERPRETATION: These results demonstrate that KIBRA regulates Abeta metabolism via controlling the secretion of APP-CTFbeta/Abeta-associated EVs. FUNDING: National Key R&D Program of China, and National Natural Science Foundation of China. |
