Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ, 85013, USA.
Department of Pathology and Laboratory Medicine, Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA.
Acta Neuropathol Commun. 2022 Jun 8;10(1):86. doi: 10.1186/s40478-022-01385-w.
Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.
尽管唐氏综合征（DS）是智力障碍最常见的发育性遗传原因，但其在产前额叶皮层（FC）中表现出增殖和迁移缺陷，但对于 21 三体对产后皮质发育的影响仍存在知识空白。在这里，我们通过应用双皮质素（DCX）、非磷酸化高分子神经丝蛋白（NHF，SMI-32）、钙结合蛋白 D-28K（Calb）、钙调蛋白（Calr）和 parvalbumin（Parv）抗体，以及β-淀粉样蛋白（APP/Aβ 和 Aβ）和磷酸化 tau（CP13 和 PHF-1），在从 28 周龄（wk）妊娠到 3 岁的年龄匹配的 DS 和神经典型（NTD）受试者的尸检组织中检查了 FC 超颗粒（SG，II/III）和内颗粒（IG，V/VI）层的神经发生和分化。硫堇染色显示，皮层细胞层排列紊乱，包括在 DS 中直到 44 周龄才出现的锥体细胞出现延迟，而在 NTD 中则为 28 周龄。在 NTD 中，直到 83 周龄，在 DS 中直到 57 周龄，才能在最年轻的病例中观察到 SG 和 IG 的 DCX-免疫反应（ir）细胞。在最年长的 NTD 和 DS 病例中，观察到强烈的 SMI-32 免疫反应，III 和 V 层的锥体细胞，而在 NTD 中，早在 28 周龄时就出现了少数 V 层的锥体细胞。与老年受试者相比，在年轻的 NTD 和 DS 病例中可以看到较小的 Calb-ir 中间神经元。总体而言，在 NTD 中检测到更多的 Calb-ir 细胞，而在两组之间 Calr-ir 细胞的数量相当。在两组中，在所有年龄段都发现了弥漫性 APP/Aβ 免疫反应。来自两组的少数年轻病例在 I 层中出现非神经元颗粒 CP13 免疫反应。在 NTD 中发现了大脑重量、年龄、硫堇、DCX 和 SMI-32 计数之间更强的相关性。这些发现表明，21 三体影响产后 FC 分层、神经元迁移/神经发生以及投射神经元和中间神经元的分化，这可能导致 DS 中的认知障碍。
