alexa Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Down Syndrome & Chromosome Abnormalities

Author(s): Boeras DI, Granic A, Padmanabhan J, Crespo NC, Rojiani AM

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Abstract

Mutations in the presenilin 1 gene cause most early onset familial Alzheimer's disease (FAD). Here, we report that a defect in the cell cycle - improper chromosome segregation - can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: (1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knocking mice are aneuploid by metaphase chromosome analysis and in situ hybridization. (2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 h, including trisomy 21. (3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.

This article was published in Neurobiol Aging and referenced in Journal of Down Syndrome & Chromosome Abnormalities

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