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KIBRA regulates amy...
KIBRA regulates amyloid β metabolism by controlling extracellular vesicles secretion
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Han, Xiaolei (författare)
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Wang, Chaoqun (författare)
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Song, Lin (författare)
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visa fler...
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Wang, Xiaojie (författare)
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Tang, Shi (författare)
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Hou, Tingting (författare)
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- Liu, Cuicui (författare)
- Karolinska Institutet
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Liang, Xiaoyan (författare)
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- Qiu, Chengxuan (författare)
- Stockholms universitet,Centrum för forskning om äldre och åldrande (ARC), (tills m KI),Shandong University, China
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Wang, Yongxiang (författare)
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Du, Yifeng (författare)
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska.
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 78
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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 β (Aβ) metabolism and transmission during Alzheimer's disease (AD) pathogenesis. Here, we further test the hypothesis that KIBRA regulates Aβ 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 Aβ 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 Aβ levels were analyzed using multiple-PCR amplification and Simoa, respectively.Findings Multiple forms of Aβ 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 β (APP-CTFβ)/Aβ levels. KIBRA depletion also decreased APP-CTFβ/Aβ-associated EVs secretion and subsequently enhanced MVBs number. Furthermore, we found that excessive accumulation of MVBs harboring APP-CTFβ/Aβ promoted the MVBs-lysosome fusion for degradation and inhibition of lysosomal function rescued secretion of APP-CTFβ/Aβ-associated EVs. More importantly, whole exon sequencing of KIBRA in a large population-based cohort identified the association of KIBRA rs28421695 polymorphism with plasma Aβ levels.Interpretation These results demonstrate that KIBRA regulates Aβ metabolism via controlling the secretion of APP-CTFβ/Aβ-associated EVs.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- Extracellular vesicles
- Lysosomes
- KIBRA
- Amyloid β
- Alzheimer’s disease
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Han, Xiaolei
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Wang, Chaoqun
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Song, Lin
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Wang, Xiaojie
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Tang, Shi
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Hou, Tingting
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visa fler...
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Liu, Cuicui
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Liang, Xiaoyan
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Qiu, Chengxuan
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Wang, Yongxiang
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Du, Yifeng
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Neurologi
- Artiklar i publikationen
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EBioMedicine
- Av lärosätet
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Stockholms universitet
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Karolinska Institutet