Regional alterations in amyloid precursor protein and nerve growth factor across age in a mouse model of Down's syndrome

Abstract

Individuals with Down's syndrome (DS) develop the pathological hallmarks of Alzheimer's (AD) disease at an early age, subsequently followed by memory decline and dementia. We have utilized an animal model for DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), to study biological events linked to memory loss. Previous studies demonstrated a cognitive decline and loss of cholinergic markers after 6–8 months of age. In the current study, we found increased levels of amyloid precursor protein (APP) in the striatum by 6–8 months of age, and in the hippocampus and parietal cortex by 13–16 months of age in Ts65Dn but not in normosomic mice. Additionally, Ts65Dn mice exhibited alterations in nerve growth factor (NGF) levels in the basal forebrain and hippocampus. Ts65Dn mice demonstrated a significant decline in NGF levels in the basal forebrain with age, as well as a reduction in hippocampal NGF by 13–16 months of age. These findings demonstrate that elevated APP and decreased NGF levels in limbic areas correlate with the progressive memory decline and cholinergic degeneration seen in middle-aged trisomic mice.