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Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. 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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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.
References:
Bernis C, Vigneron S, Burgess A, Labbé JC, Fesquet D, Castro A, Lorca T. Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp). EMBO Rep. 2007 Jan;8(1):91-8. PubMed.
Machida YJ, Dutta A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 2007 Jan 15;21(2):184-94. PubMed.
Kim MY, Jeong BC, Lee JH, Kee HJ, Kook H, Kim NS, Kim YH, Kim JK, Ahn KY, Kim KK. 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.
Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H, Hashimoto R, Tanaka T, Kudo T, Yamagata H, Tabara Y, Miki T, Akatsu H, Kosaka K, Funakoshi E, Nishitomi K, Sakaguchi G, Kato A, Hattori H, Uema T, Takeda M. 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.
Kulartz M, Hiller E, Kappes F, Pinna LA, Knippers R. Protein kinase CK2 phosphorylates the cell cycle regulatory protein Geminin. Biochem Biophys Res Commun. 2004 Mar 19;315(4):1011-7. PubMed.
Ayté J, Schweitzer C, Zarzov P, Nurse P, DeCaprio JA. Feedback regulation of the MBF transcription factor by cyclin Cig2. Nat Cell Biol. 2001 Dec;3(12):1043-50. PubMed.
Zhu W, Dutta A. 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.
Welcsh PL, Lee MK, Gonzalez-Hernandez RM, Black DJ, Mahadevappa M, Swisher EM, Warrington JA, King MC. BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7560-5. PubMed.
Arendt T, Brückner MK. Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity. Biochim Biophys Acta. 2007 Apr;1772(4):413-21. PubMed.
Araki M, Wharton RP, Tang Z, Yu H, Asano M. 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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