产前给予油酸或亚麻酸可减少 Ts65dn 唐氏综合征小鼠的神经形态和认知改变。

Prenatal Administration of Oleic Acid or Linolenic Acid Reduces Neuromorphological and Cognitive Alterations in Ts65dn Down Syndrome Mice.

机构信息

Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Cantabria, Spain.

Institute of Molecular Biology and Biomedicine (IBTECC), Santander, Cantabria, Spain.

出版信息

J Nutr. 2020 Jun 1;150(6):1631-1643. doi: 10.1093/jn/nxaa074.

DOI:10.1093/jn/nxaa074

PMID:32243527

Abstract

BACKGROUND

The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus, enhancing prenatal neurogenesis in DS could prevent or reduce some of the neuromorphological and cognitive defects found in postnatal stages.

OBJECTIVES

As fatty acids play a fundamental role in morphogenesis and brain development during fetal stages, in this study, we aimed to enhance neurogenesis and the cognitive abilities of the Ts65Dn (TS) mouse model of DS by administering oleic or linolenic acid.

METHODS

In total, 85 pregnant TS females were subcutaneously treated from Embryonic Day (ED) 10 until Postnatal Day (PD) 2 with oleic acid (400 mg/kg), linolenic acid (500 mg/kg), or vehicle. All analyses were performed on their TS and Control (CO) male and female progeny. At PD2, we evaluated the short-term effects of the treatments on neurogenesis, cellularity, and brain weight, in 40 TS and CO pups. A total of 69 TS and CO mice were used to test the long-term effects of the prenatal treatments on cognition from PD30 to PD45, and on neurogenesis, cellularity, and synaptic markers, at PD45. Data were compared by ANOVAs.

RESULTS

Prenatal administration of oleic or linolenic acid increased the brain weight (+36.7% and +45%, P < 0.01), the density of BrdU (bromodeoxyuridine)- (+80% and +115%; P < 0.01), and DAPI (4',6-diamidino-2-phenylindole)-positive cells (+64% and +22%, P < 0.05) of PD2 TS mice with respect to the vehicle-treated TS mice. Between PD30 and PD45, TS mice prenatally treated with oleic or linolenic acid showed better cognitive abilities (+28% and +25%, P < 0.01) and a higher density of the postsynaptic marker PSD95 (postsynaptic density protein 95) (+65% and +44%, P < 0.05) than the vehicle-treated TS animals.

CONCLUSION

The beneficial cognitive and neuromorphological effects induced by oleic or linolenic acid in TS mice suggest that they could be promising pharmacotherapies for DS-associated cognitive deficits.

摘要

背景

唐氏综合征（DS）的认知障碍归因于胎儿期神经发生受损导致的脑细胞减少。因此，在 DS 中增强产前神经发生可以预防或减少出生后阶段发现的一些神经形态和认知缺陷。

目的

由于脂肪酸在胎儿期的形态发生和大脑发育中起着重要作用，因此在这项研究中，我们旨在通过给予油酸或亚麻酸来增强 DS 的 Ts65Dn（TS）小鼠模型的神经发生和认知能力。

方法

总共对 85 只怀孕的 TS 雌性进行了皮下治疗，从胚胎期 10 天（ED）到出生后 2 天（PD），给予油酸（400mg/kg）、亚麻酸（500mg/kg）或载体。所有分析均在其 TS 和对照（CO）雄性和雌性后代中进行。在 PD2 时，我们评估了治疗对 40 只 TS 和 CO 幼崽的神经发生、细胞数和脑重的短期影响。共有 69 只 TS 和 CO 小鼠用于测试产前治疗对 PD30 至 PD45 的认知、PD45 的神经发生、细胞数和突触标记物的长期影响。数据通过方差分析进行比较。

结果

产前给予油酸或亚麻酸可使 TS 幼鼠的脑重增加（+36.7% 和+45%，P<0.01），BrdU（溴脱氧尿苷）-阳性细胞密度增加（+80% 和+115%；P<0.01），DAPI（4'，6-二脒基-2-苯基吲哚）-阳性细胞增加（+64% 和+22%，P<0.05）。在 PD30 至 PD45 之间，用油酸或亚麻酸预处理的 TS 小鼠的认知能力更好（+28% 和+25%，P<0.01），突触后标记物 PSD95（突触后密度蛋白 95）的密度更高（+65% 和+44%，P<0.05）比用载体处理的 TS 动物。