Title:Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease
Volume: 13
Issue: 1
Author(s): Huntington Potter, Antoneta Granic and Julbert Caneus
Affiliation:
Keywords:
Alzheimer’s disease, down syndrome, mitosis, aneuploidy, trisomy 21, neurogenesis.
Abstract: Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and
increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s
disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy
21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and
familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two
sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss
of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the
pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons
and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal
lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that
Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific
microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize
and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention.
For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy
21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated
with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
