Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons

Gui-Zhi Yang, Miao Yang, Yoon Lim, Jianjun Lu, Ting-Hua Wang, Jian-Guo Qi, Jin Hua Zhong, Xin-Fu Zhou

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease. It is axonally transported, endocytosed and sorted to different cellular compartments where amyloid beta (Aβ) is produced. However, the mechanism of APP trafficking remains unclear. We present evidence that huntingtin associated protein 1 (HAP1) may reduce Aβ production by regulating APP trafficking to the non-amyloidogenic pathway. HAP1 and APP are highly colocalized in a number of brain regions, with similar distribution patterns in both mouse and human brains. They are associated with each other, the interacting site is the 371-599 of HAP1. APP is more retained in cis-Golgi, trans-Golgi complex, early endosome and ER-Golgi intermediate compartment in HAP1-/- neurons. HAP1 deletion significantly alters APP endocytosis and reduces the re-insertion of APP into the cytoplasmic membrane. Amyloid precursor protein-YFP(APP-YFP) vesicles in HAP1-/- neurons reveal a decreased trafficking rate and an increased number of motionless vesicles. Knock-down of HAP1 protein in cultured cortical neurons of Alzheimer's disease mouse model increases Aβ levels. Our data suggest that HAP1 regulates APP subcellular trafficking to the non-amyloidogenic pathway and may negatively regulate Aβ production in neurons.

    Original languageEnglish
    Pages (from-to)1010-1022
    Number of pages13
    JournalJournal of Neurochemistry
    Volume122
    Issue number5
    DOIs
    Publication statusPublished - Sep 2012

    Keywords

    • amyloid beta
    • amyloid precursor protein
    • huntingtin associated protein
    • trafficking

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