. Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning. Neurobiol Dis. 2009 May;34(2):212-20. PubMed.

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  1. Alzheimer’s disease is a mosaic form of Down syndrome. The data supporting this conclusion have been building in several laboratories, culminating in the excellent work just published by Iourov and colleagues.

    The story began with a hypothesis that small numbers of trisomy 21 cells are present in the brains of AD patients and contribute to their neurodegenerative disease just as Down syndrome individuals with trisomy 21 in all of their cells acquire AD pathology at an early age. Furthermore, mutant genes that cause inherited AD were proposed to induce chromosome missegregation and aneuploidy, including trisomy 21.

    All of these predictions have now been fulfilled. First, fibroblasts and lymphocytes, and more recently buccal cells, collected from both sporadic AD patients and those with mutations is PS1 and APP, were found to include significant numbers of trisomy 21 cells. Then, aneuploidy, including trisomy 21, and some overall tetraploidy were reported in neurons from AD patients. Some authors focused primarily on the tetraploidy as indicative of a failed attempt by neurons to re-enter the cell cycle, resulting in degeneration, while we and others focused on the trisomy 21 as indicative of a somatic tendency to chromosome missegregation. Recently, families in which only the APP gene on one chromosome 21 is duplicated have been found to develop early-onset FAD, reinforcing the concept that three copies of APP are the AD-relevant feature of trisomy 21/Down syndrome.

    To avoid the difficulty and artifacts inherent in some previous analyses of tissue sections, Iourov and colleagues counted chromosomes in isolated nuclei from normal and AD subjects using two forms of multicolor Fluorescence In Situ Hybridization (FISH). Their data show that neither AD neurons (neuN+) nor glia (NeuN-) exhibited an increase in full tetraploidy, but the AD neurons showed a “dramatic 10-fold increase in trisomy 21-specific aneuploidy” (both monosomy and trisomy) compared to neurons from age-matched controls.

    The authors also found a more general neuronal aneuploidy affecting all measured chromosomes in 20 to 50 percent of neurons from ataxia telangiectasia patients. This finding, together with the recent report by Rossi and colleagues of chromosome missegregation and aneuploidy in patients with frontotemporal dementia, supports our earlier prediction that chromosome missegregation may underlie many neurodegenerative diseases of aging as it may contribute to many forms of cancer.

    The mechanism by which chromosome missegregation arises in and contributes to AD is currently under investigation. We reported in the last several Society for Neuroscience and ICAD meetings that the Aβ peptide itself has aneugenic activity, and certainly the oxidative stress, abnormal calcium entry, and defective microtubule transport reported in AD are likely to affect the mitotic spindle, and/or mitotic checkpoint, and affect chromosome segregation. Defective neurogenesis, as has been found in AD transgenic mice, is also likely to be defective if neuronal precursor cells are suffering from chromosome missegregation.

    In sum, the conclusion of the paper by Iourov et al. and its predecessors is that:

    Chromosome aneuploidy, specifically trisomy 21

    1. arises in AD brain and peripheral tissues;
    2. likely contributes to the disease;
    3. may serve as a valuable biomarker of AD; and
    4. may form the basis of novel therapies aimed at preventing the development or the downstream effects of trisomy 21.

    References:

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    . Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell. 1997 Sep 5;90(5):917-27. PubMed.

    . Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients. Cytogenet Cell Genet. 1999;87(1-2):41-6. PubMed.

    . Aneuploidy and DNA replication in the normal human brain and Alzheimer's disease. J Neurosci. 2007 Jun 27;27(26):6859-67. PubMed.

    . Review and hypothesis: Alzheimer disease and Down syndrome--chromosome 21 nondisjunction may underlie both disorders. Am J Hum Genet. 1991 Jun;48(6):1192-200. PubMed.

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    . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. PubMed.

    . APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain. 2006 Nov;129(Pt 11):2977-83. PubMed.

    . Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease. Mutagenesis. 2008 Jan;23(1):57-65. PubMed.

    . DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001 Apr 15;21(8):2661-8. PubMed.