Certain abnormal conditions that affect the nervous system --- collectively known as neurodegenerative diseases --- are associated with cognitive impairment due to neuronal dysfunction and loss in the affected brain regions. However, the mechanisms underlying these defects remain poorly understood. Previous studies have shown that every person with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by the age of 40 years, and that the majority go on to develop dementia. Furthermore, studies from our laboratory and others have demonstrated that people with AD have increased levels of mosaic aneuploidy, including trisomy 21, in both brain and peripheral cells. These findings, combined with the fact that most of these conditions include neuronal degeneration and cognitive decline as common pathological and clinical characteristics, led to our hypothesis that abnormal chromosome segregation resulting in aneuploidy may be a common underlying mechanism in the pathogenesis of other neurodegenerative diseases beyond AD. To test our hypothesis, we analyzed aneuploidy levels in brain cells from patients with familial frontotemporal lobar degeneration (FTLD) who carry a mutation in either the MAPT (Tau) or the progranulin (PGRN) gene or from patients with sporadic FTLD, compared to aneuploidy in brains of aged matched controls. We also analyzed karyotypically normal human cell lines transfected (and untransfected) with vectors for expression of FTLD-causing mutant forms of the human MAPT gene or with PGRN-shRNA, and brain cells from mouse models of FTLD that express mutant MAPT, compared to litter mate controls. In 2010, Arendt and colleagues showed that the death of aneuploid/hyperploid cells in AD accounts for 90% of neuronal cell loss from the mild cognitive impairment stage to late stage AD [2]. Based on these findings, we also determined the percentage of aneuploid versus euploid cells that undergo apoptosis in an effort to better understand the effect(s) of aneuploidy on neurodegenerative disease progression. Collectively, our results revealed a significant increase in the percentage of aneuploidy in brain cells from all types of FTLD patients, in human cell lines transfected with vectors for expression of FTLD-causing mutant forms of human MAPT or with PGRN-shRNA, and in mouse models of FTLD that express mutant MAPT compared to normal controls respectively. Additionally, both brain cells from FTLD patients and cell lines expressing FTLD-causing mutant forms of human MAPT exhibited significantly higher levels of apoptotic cells relative to negative controls. Our data also showed significantly increased levels of apoptosis in aneuploid cells compared to diploid cells, and our analyses of mitotic spindles demonstrated a significant increase in abnormal spindles in the cell lines expressing FTLD-causing mutant forms of human MAPT relative to negative controls. Taken together, our findings indicate that defects in mitotic spindle formation can result in aneuploidy that promotes cell death and ultimately plays an important role in the progression of multiple neurodegenerative diseases. Therefore, a better understanding of the mechanism(s) by which aneuploidy arises and of its role in the initiation and progression of neurodegenerative diseases will establish a strong foundation for the development of novel preventative therapeutics.

1. Arendt, T., et al., Selective cell death of hyperploid neurons in Alzheimer's disease. Am J Pathol, 2010. 177(1): p. 15-20.