ALZHEIMER’S DISEASE IN DOWN SYNDROME CAN BE PREVENTED BY PHARMACOLOGIC TREATMENT DURING PRENATAL TO EARLY POSTNATAL DEVELOPMENT

Abstract

Alzheimer's disease (AD) is a multifactorial disorder. Down syndrome (DS) which is caused by trisomy 21, is one of the etiopathogenic mechanisms of AD. By the age 40, almost all DS individuals develop the histopathological characteristics of AD, and ∼70% of them develop dementia by age 60. The Ts65Dn trisomic mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment and synaptic loss. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. We treated Ts65Dn mice from embryonic day 8 (E8) to weaning/postnatal day 21 with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, the compound P021 (200 nmoles/g diet administered to mothers/dams) and studied developmental milestones and during adult life cognitive performance. We found that Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life (5–7 months of age) in Ts65Dn mice. Furthermore, this treatment prevented synaptic loss and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (∼ 7-monthold) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments and that AD can be a developmental defect with a late life onset.