Down syndrome-associated trisomic chromosomal regions modify amyloid-β accumulation and cause early death in a mouse model of aspects of Alzheimer's disease

Abstract

Background Individuals with Down syndrome (DS), caused by triplication of chromosome 21 (Hsa21), face a significantly increased risk of early-onset Alzheimer's disease (AD) and epilepsy. However, the specific impact of Hsa21 genes on these risks is not yet fully understood. Objective To investigate how triplication of mouse chromosome 16 (Mmu16), homologous to Hsa21, affects amyloid-β (Aβ) accumulation in the brain and epileptic seizures in AD-DS model mice. Methods To generate AD-DS model mice, we crossed a mouse model of aspects of AD—an APPswe/PS1dE9 mouse exhibiting brain Aβ accumulation and sudden death associated with epileptic seizures with DS mouse models carrying an extra copy of partial segments of mouse chromosome 16. We used three DS model lines: Ts1Cje, harboring a triplicated region encoding ∼70 Hsa21-homologous genes (Scaf4-Zbtb21); Ts1Rhr with triplication of the Cbr3-Fam3b region; and a newly developed Ts1Kei mouse carrying an extra copy of the Scaf4-Cbr1 region. Aβ accumulation was assessed by immunohistochemistry and enzyme-linked immunosorbent assay. Results Compared with APPswe/PS1dE9 mice, Aβ deposition and insoluble Aβ levels in the brain decreased in APPswe/PS1dE9-Ts1Cje mice but not in APPswe/PS1dE9-Ts1Rhr mice. The high mortality in APPswe/PS1dE9 mice was suppressed by either Ts1Cje- or Ts1Rhr-triplicated region. Despite a tendency for decreased Aβ accumulation in APPswe/PS1dE9-Ts1Kei mice, the study could not be finished due to the extremely high mortality. Conclusions The trisomic region in Ts1Kei mice is suggested to harbor genes associated with decreased Aβ accumulation. Alternatively, the trisomic region in Ts1Rhr mice contains genes suppressing sudden death in APPswe/PS1dE9 mice.