. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):796-807. PubMed.


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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.


    . Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp). EMBO Rep. 2007 Jan;8(1):91-8. PubMed.

    . The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 2007 Jan 15;21(2):184-94. PubMed.

    . A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13074-9. Epub 2006 Aug 21 PubMed.

    . The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet. 2007 Jan 1;16(1):15-23. PubMed.

    . Protein kinase CK2 phosphorylates the cell cycle regulatory protein Geminin. Biochem Biophys Res Commun. 2004 Mar 19;315(4):1011-7. PubMed.

    . Feedback regulation of the MBF transcription factor by cyclin Cig2. Nat Cell Biol. 2001 Dec;3(12):1043-50. PubMed.

    . An ATR- and BRCA1-mediated Fanconi anemia pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication. Mol Cell Biol. 2006 Jun;26(12):4601-11. PubMed.

    . BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7560-5. PubMed.

    . Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity. Biochim Biophys Acta. 2007 Apr;1772(4):413-21. PubMed.

    . Degradation of origin recognition complex large subunit by the anaphase-promoting complex in Drosophila. EMBO J. 2003 Nov 17;22(22):6115-26. PubMed.

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