Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-08-06 DOI:10.1007/s00401-024-02768-0
Melissa J. Alldred, Harshitha Pidikiti, Kyrillos W. Ibrahim, Sang Han Lee, Adriana Heguy, Gabriel E. Hoffman, Panos Roussos, Thomas Wisniewski, Jerzy Wegiel, Grace E. Stutzmann, Elliott J. Mufson, Stephen D. Ginsberg
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Abstract

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer’s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

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对额叶皮层兴奋层 III 和 V 锥体神经元的微分离分析显示了唐氏综合征患者的神经退行性表型。
我们阐明了唐氏综合征(DS)患者特定皮层内脆弱兴奋神经元的分子指纹,以便从机理上了解阿尔茨海默病(AD)的病理生理学,并挖掘其治疗潜力。从死后人类唐氏综合征患者和年龄与性别匹配的对照组(CTR)中微分离出额叶皮层(BA9)第III层(L3)和第V层(L5)锥体神经元,以研究与神经退行性疾病相关的差异表达基因(DEGs)和关键生物通路。我们在 DS 患者与 CTR 受试者的 L3 和 L5 锥体神经元中发现了超过 2300 个 DEGs,这些 DEGs 表现出基因表达的趋同失调。在L3和L5神经元中,DEGs包括100多个人类21号染色体三倍体基因,这表明在两个神经元层中都存在三体神经元核型。此外,还发现了数千个其他DEGs,这表明基因失调并不局限于老年DS大脑中的三体基因,我们推测这与AD病理生物学有关。L3和L5 DEGs的融合突显了相关的生物通路,并确定了可能是DS患者皮质神经变性和相关认知能力下降的关键通路相关靶点。研究人员选择了一些关键的 DEGs 作为驱动失调的潜在枢纽基因,即三重 DEGs 淀粉样前体蛋白(APP)和超氧化物歧化酶 1(SOD1),以及关键的信号转导 DEGs,包括丝裂原活化蛋白激酶 1 和 3(MAPK1、MAPK3)以及钙调蛋白依赖性蛋白激酶 II alpha(CAMK2A)等。通过多通路分析确定的枢纽 DEGs 确定了改善 DS 皮质神经元功能障碍和认知能力下降的潜在候选疗法,这些候选疗法与 AD 具有转化相关性。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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