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P1‐178: SYNAPTIC MEMBRANE CHOLESTEROL: CULPRIT OR ACCOMPLICE OF ALZHEIMER'S DISEASE?
Author(s) -
Zhang Qi
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.733
Subject(s) - amyloid precursor protein , synaptic vesicle , microbiology and biotechnology , cleavage (geology) , intracellular , alpha secretase , amyloid precursor protein secretase , chemistry , alzheimer's disease , p3 peptide , vesicle , biology , neuroscience , biochemistry , membrane , medicine , disease , paleontology , fracture (geology)
Background: Alcadein a (Alca) is a neuronal type I membrane protein and functions as a cargo of kinesin-1. Alca forms a tripartite complex with APP by mediation of neuronal adaptor protein X11-like (X11L) [1-3]. We previously reported that amyloidogenic processing of APP increased in X11L knockout mice brain [4-6]. Because Alca increases the binding of APP with X11L in vitro, we explored the role of Alcain APP processing in brain. Methods: Alca gene knockout (Alca-KO) mice are generated, and the endogenous APP processing and Ab generation in the brain were analyzed. The Alca-KO mice were mated with APP23 mice to generate human APP-Tg/Alca-KO mice and the amyloid plaque formation of Tg/KO mice brain was analyzed by immunostaining. Results: APP expression was not altered in Alca-KO mice compared to wild-type (WT) mice. Levels of CTFb/C99 and CTFb’/C89 of APP increased significantly in the brain of AlcaKO mice, while the level of APP CTFa/C83 did not change compared to the WT mice. The number of amyloid plaques increased significantly in APP-Tg/Alca-KO mice when compared to APP-Tg mice. In coimmunoprecipitation assay of APP with X11L in brain lysates, lesser amount of APP was recovered from Alca-KO mice brain compared to those of WT mice. Conclusions: Our previous reports indicate that the deficiency of X11L increases b-site cleavage of APP in brain. Therefore, attenuated association of APP with X11L in Alcadeficient mice may enhance the amyloidogenic processing of APP, supporting our idea that Alca is involved in AD pathobiology [7, 8]. 1. Araki et al., (2003) J. Biol. Chem. 278, 49448; 2. Araki et al., (2007) EMBO J. 26, 1475; 3. Sobu et al., (2017) Mol. Biol. Cell 28, 3844; 4. Sano et al., (2006) J. Biol. Chem. 281, 37853; 5. Saito et al., (2008) J. Biol. Chem. 281, 35763; 6. Kondo et al., (2010)Mol. Neurodegener. 5, 35; 7. Hata et al., (2009) J. Biol. Chem. 284, 36024; 8. Hata et al., (2011) Ann. Neurol. 69, 1026.