Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras, Debrah I.; Granic, Antoneta; Padmanabhan, Jaya; Crespo, Nichole C.; Rojiani, Amyn M.; Potter, Huntington

doi:10.1016/j.neurobiolaging.2006.10.027

« Previous Next »Neurobiology of Aging
Volume 29, Issue 3 , Pages 319-328, March 2008

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Debrah I. Boeras
- Department of Molecular Medicine and Suncoast Gerontology Center, University of South Florida, College of Medicine, Tampa, FL 33612, USA
- Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Tampa, FL 33647, USA
- Present address: Emory University, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
Antoneta Granic
- Department of Molecular Medicine and Suncoast Gerontology Center, University of South Florida, College of Medicine, Tampa, FL 33612, USA
- Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Tampa, FL 33647, USA
Jaya Padmanabhan
- Department of Molecular Medicine and Suncoast Gerontology Center, University of South Florida, College of Medicine, Tampa, FL 33612, USA
- Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Tampa, FL 33647, USA
Nichole C. Crespo
- Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Tampa, FL 33647, USA
Amyn M. Rojiani
- Department of Pathology, University of South Florida College of Medicine, Tampa, FL 33612, USA
Huntington Potter
- Department of Molecular Medicine and Suncoast Gerontology Center, University of South Florida, College of Medicine, Tampa, FL 33612, USA
- Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Tampa, FL 33647, USA
- H.Lee Moffitt Cancer Center, Tampa, FL 33612, USA
- Corresponding author at: Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, 15130 Amberly Drive, Tampa, FL 33647, USA. Tel.: +1 813 866 1600; fax: +1 813 866 1601.

Received 29 June 2006; received in revised form 27 September 2006; accepted 25 October 2006. published online 14 December 2006.

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 knockin 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 48h, 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.