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  1. The study by Biswas and colleagues supporting the role of miscreant cell cycle proteins in Aβ toxicity is interesting.

    Dysregulation of the cell cycle would seem to be a significant factor in AD. PIN1, which is downregulated by oxidation in AD neurons and is involved in APP processing, has recently been found to protect Emi1 (anaphase-promoting complex (APC) early mitotic inhibitor 1) from degradation [1]. Emi1 is essential for prevention of rereplication, as is geminin, an interactor with the SWI-SNF complex which has been found to be reduced in the DS fetal brain. Rereplication seen after Emi1 depletion is due to premature activation of APC/C that results in destabilization of geminin [2]. Kim et al. [3] report AP4 and geminin act as a repressor complex that regulates expression of target genes including DYRK1A. In view of the fact that DYRK1A is also reported to be increased in AD, might we suspect reduced geminin [4]? Geminin is an inhibitor of Cdt1p. Ayte and colleagues report that increased expression of Cdc18p and Cdt1p in G2 phase results in endoreduplication and polyploidy 21 [5,6]. Perhaps the increased Cdt1p and reduced geminin may explain DS and the trisomy 21 mosaicism in AD.

    Zhu and Dutta [7] report that rereplication activates the ATR and BRCA1-mediated Fanconi anemia pathway. Of interest is that APP is significantly upregulated on induction of BRCA1 [8].

    Arendt and Bruckner [9] suggest a tight association of the origin recognition complex (ORC) with neurofibrillar pathology in AD. It's of interest that Araki and colleagues [10] find that the anaphase-promoting complex degrades the origin recognition complex large subunit in Drosophila.

    View all comments by Mary Reid

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  1. Aβ—Three Places, Three Ways of Wreaking Havoc