Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer\u2019s-like memory deficits in the Ts65Dn mouse model of Down syndrome

Syed Faraz Kazim,Syed Faraz Kazim,Syed Faraz Kazim,Riccardo Bianchi,Julie Blanchard,Khalid Iqbal

doi:10.1038/srep45561

Syed Faraz Kazim, Syed Faraz Kazim + Show 4 more

Open Access

https://doi.org/10.1038/srep45561

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Abstract

Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of intellectual disability and is associated with a greatly increased risk of early-onset Alzheimer’s disease (AD). The Ts65Dn mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment. Accumulating evidence suggests that impairments in early brain development caused by trisomy 21 contribute significantly to memory deficits in adult life in DS. 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. Here, we report that prenatal to early postnatal treatment with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life in Ts65Dn mice. Furthermore, this treatment prevented pre-synaptic protein deficit, decreased glycogen synthase kinase-3beta (GSK3β) activity, 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-month-old) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments in a DS mouse model.

Highlights

Mimic the human condition presenting developmental delay in motor and sensory milestones[18,21]
We found that Peptide 021 (P021) acted via dose-dependent competitive inhibition of leukemia inhibitory factor (LIF) activity towards LIF/ciliary neurotrophic factor (CNTF) receptor at as low as 0.1 nM (p < 0.05 at 10 nM P021) concentration as measured by phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr70569
Previously we showed that oral administration of P021 in the diet decreased the phosphorylation of STAT3 at pTyr[705] in the hippocampus of 3xTg-Alzheimer’s disease (AD) mice and the age-matched wild type controls after 6 months of treatment[67]

Summary

Introduction

Mimic the human condition presenting developmental delay in motor and sensory milestones[18,21]. Like human DS individuals, these mice demonstrate impaired ontogenic neurogenesis[22], possibly a major factor responsible for aberrant brain development and cognitive dysfunction. During the past few years, a growing number of studies have explored the exciting possibility of using pharmacological approaches to ameliorate neurodevelopmental deficits in DS mouse models during the critical time window of brain development, and shown significant improvement in learning and memory in adult life (for review, refs 40, 41, 42 and 44). After the critical window of brain development including neurogenesis and synaptogenesis which takes place during prenatal and early postnatal period, the brain can undergo limited plastic changes, and the late therapies are unlikely to exert profound and long lasting effects in DS brains[40,41,42,44]. Neurotrophic factor small-molecule mimetics, which can exert the therapeutic beneficial effects of neurotrophic factors on neurogenesis, neuronal and synaptic plasticity, and cognition, and have favorable pharmacokinetics and BBB permeability without unwanted systemic effects, offer a promising strategy to overcome the limitations associated with therapeutic usage of whole-molecule recombinant neurotrophic factors[63,64,65]

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