Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients

Abstract

To further investigate our finding of high levels of spontaneous aneuploidy in somatic cells of Alzheimer’s disease (AD) patients (Migliore et al. 1997), we studied the molecular cytogenetics of eight patients with sporadic AD and six healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral blood lymphocytes from the AD patients and unaffected controls were used to measure micronucleus induction or other aneuploidy events, such as the presence of malsegregation in interphase nuclei (representing chromosome loss and gain). Dual-color fluorescence in situ hybridization (FISH) with differential labeled DNA probes was applied. We used a probe specific for the centromeres of chromosomes 13 and 21 combined with a single cosmid for the Down’s syndrome region (21q22.2) to obtain information on spontaneous chromosome loss and gain frequencies for both chromosomes (13 and 21). FISH data showed that AD lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently labeled micronuclei) for both chromosomes, as well as higher frequencies of aneuploid interphase nuclei, again involving both chromosomes, compared to control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than for chromosome 13 in AD patients. This preferential occurrence of chromosome 21 in malsegregation in somatic cells of AD patients raises the hypothesis that mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in AD patients, as well as in elderly Down’s syndrome patients.

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

“…Furthermore, women who have a Downs syndrome/ trisomy 21 child before the age of 35 are usually aneuploid for trisomy 21 themselves and have a five-fold increased risk of developing AD later in life [26,37,38]. These findings indicate that overexpression or an extra copy of normal APP, either in Down syndrome, in the duplicated APP families, or because of spontaneous or PS-induced trisomy 21 mosaicism can lead to AD.…”

“…For example, as mentioned in the introduction, significant numbers of trisomy 21 and other aneuploid cells have been found in both sporadic and familial AD patients, including individuals carrying a mutation in PS-1 or PS-2 [9,26,31,49,50]. Similarly, two polymorphisms in PS-1, one in the coding sequence and one in the promoter have been found to be associated with both an increased risk of AD and an increased incidence of Down syndrome offspring due to chromosome missegregation during meiosis [24,29].…”

“…One key function of the PS proteins is to contribute to the γ-secretase enzyme, which cleaves the amyloid precursor protein (APP) in its transmembrane region to generate the C-terminus of the Aβ peptide, the major component of the amyloid deposits in the Alzheimer brain. Most FAD mutations in PS-1 or 2 change the specificity of the γ-secretase enzyme such that there is increase the production of a highly amyloidegenic class of Aβ peptide, Aβ x-42 , compared to the more common Aβ x-40 [5,11,12,27,47] Several lines of evidence indicate that abnormalities in one or more aspects of the cell cycle may contribute to AD pathogenesis [1,9,14,26,28,30,31,32,42,49,50]. For example, many sporadic and familial AD patients, including those carrying presenilin mutations, exhibit a defect in chromosome segregation that leads to aneuploidy, including trisomy 21, in many cells throughout the body [10,26,30,31,49,50].…”

Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics?

“…Using a scientific approach quite different from approaches used to date, work done on the alterations of centromere dynamics in interphase nuclei of neuronal cells and peripheral blood lymphocytes of AD patients [30][31][32] have confirmed not only that these cells undergo mitosis but that the temporal dynamics of centromeres are highly altered.…”

Multicolor Deconvolution Microscopy of Thick Biological Specimens

“…Third, there is a growing awareness that mosaicism, ie, patches of tissue that differ genetically from the rest of their body because of a chromosomal anomaly, may contribute to common conditions such as infertility, autism, and Alzheimer's disease. [5][6][7][8] Advanced single-cell tools should facilitate the identification of genetically different tissues. Fourth, rare cell events, eg, early pathological lesions in neoplasia or minimal residual disease should greatly benefit from the analysis of individual cells within their natural tissue context.…”