Department of Neurochemistry, and SUNY Downstate/NYSIBR Center for Developmental Neuroscience, New York State Institute for Basic Research (NYSIBR), Staten Island, NY 10314, USA.
The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY 11203, USA.
Sci Rep. 2017 Apr 3;7:45561. doi: 10.1038/srep45561.
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.
唐氏综合征（DS）由 21 三体引起，是智力障碍最常见的遗传原因，并且与早发性阿尔茨海默病（AD）的风险大大增加有关。Ts65Dn 唐氏综合征小鼠模型表现出该疾病的几个关键特征，包括发育迟缓以及类似 AD 的认知障碍。越来越多的证据表明，21 三体引起的早期大脑发育障碍，对 DS 患者成年后的记忆缺陷有重大影响。通过产前遗传检测来诊断宫内唐氏综合征，为针对这一关键大脑发育期的早期药物治疗提供了新的机会。在这里，我们报告说，产前至产后早期用睫状神经营养因子（CNTF）小分子肽模拟物 Peptide 021（P021）治疗，可以挽救 Ts65Dn 小鼠的发育迟缓，并改善成年期类似 AD 的海马依赖性记忆障碍。此外，这种治疗还可以预防突触前蛋白缺陷，降低糖原合酶激酶 3β（GSK3β）活性，并增加突触可塑性标志物的水平，包括脑源性神经营养因子（BDNF）和磷酸化 CREB，在年轻（3 周龄）和成年（~7 月龄）Ts65Dn 小鼠中均如此。这些发现为提供早期大脑发育期间的神经营养支持可以预防 DS 小鼠模型中的发育迟缓及 AD 样记忆障碍提供了新的证据。
