Biological Correlates of Alzheimer in Down Syndrome.

唐氏综合症中阿尔茨海默病的生物学相关性。

基本信息

批准号：
9375943
负责人：
Ann-Charlotte Esther Granholm-Bentley
金额：
$ 22.61万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9375943
关键词：
Address Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Aneuploidy Biochemistry Biological Biological Assay Biological Markers Blood Blood specimen Brain Brain region Cells Cerebrospinal Fluid Cerebrospinal Fluid Proteins Characteristics Chromosomes, Human, Pair 21 Clinical Cognitive Competence Dementia Development Diagnosis Diagnostic Diffuse Disease Down Syndrome Early Intervention Elderly Excision Exhibits Future Gene Proteins General Population Goals Head Hereditary Disease Hippocampus (Brain)Human Human Chromosomes Impaired cognition In Vitro Individual Inflammation Injectable Injection of therapeutic agent Intellectual functioning disability Investigation Lead Life Liquid substance Live Birth Manuscripts Measures Messenger RNA Methods MicroRNAs Molecular Molecular Conformation Molecular Genetics Mus Neurofibrillary Tangles Neurons Participant Pathologic Pathology Patients Penetrance Peptides Plasma Plasma Proteins Play Population Prevalence Preventive Intervention Proteins Recruitment Activity Research Personnel Risk Role Sampling Seeds Senile Plaques Signal Transduction Surface Toxic effect Trisomy Urine Vesicle Work accurate diagnosis amyloid peptide basal forebrain base brain tissue cell type cholinergic cohort design developmental genetics exosome experimental study in vivo interest interstitial mouse Ts65Dn mouse model neuropathology neurotoxic new technology novel novel marker pathogen potential biomarker pre-clinical predictive marker prion-like protein aggregate protein biomarkers rate of change tau Proteins tau aggregation tau mutation tau phosphorylation tau-1 tool

Address Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Aneuploidy Biochemistry Biological Biological Assay Biological Markers Blood Blood specimen Brain Brain region Cells Cerebrospinal Fluid Cerebrospinal Fluid Proteins Characteristics Chromosomes, Human, Pair 21 Clinical Cognitive Competence Dementia Development Diagnosis Diagnostic Diffuse Disease Down Syndrome Early Intervention Elderly Excision Exhibits Future Gene Proteins General Population Goals Head Hereditary Disease Hippocampus (Brain)Human Human Chromosomes Impaired cognition In Vitro Individual Inflammation Injectable Injection of therapeutic agent Intellectual functioning disability Investigation Lead Life Liquid substance Live Birth Manuscripts Measures Messenger RNA Methods MicroRNAs Molecular Molecular Conformation Molecular Genetics Mus Neurofibrillary Tangles Neurons Participant Pathologic Pathology Patients Penetrance Peptides Plasma Plasma Proteins Play Population Prevalence Preventive Intervention Proteins Recruitment Activity Research Personnel Risk Role Sampling Seeds Senile Plaques Signal Transduction Surface Toxic effect Trisomy Urine Vesicle Work accurate diagnosis amyloid peptide basal forebrain base brain tissue cell type cholinergic cohort design developmental genetics exosome experimental study in vivo interest interstitial mouse Ts65Dn mouse model neuropathology neurotoxic new technology novel novel marker pathogen potential biomarker pre-clinical predictive marker prion-like protein aggregate protein biomarkers rate of change tau Proteins tau aggregation tau mutation tau phosphorylation tau-1 tool

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项目摘要

ABSTRACT Down syndrome (DS) is the most common non-lethal aneuploidy in humans, caused by complete or partial trisomy of chromosome 21. In addition to intellectual disability and atypical development often observed in DS, the prevalence of dementia is significantly higher, with onset at an earlier age than in the general population. A strong candidate mechanism is the amyloid beta precursor protein (APP) gene which is located on chromosome 21 and triplicated in people with DS, giving rise to toxic amyloid peptides at an early age. Individuals with DS exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. The presence of AD pathology in younger individuals with DS is relatively unknown, due in part to a paucity of brain tissue available for study at earlier age epochs. Biomarkers that reflect AD pathology at earlier ages are thus of considerable interest since neuroprotective therapies will eventually target younger individuals with DS. Most cell types in the body, including neurons, release small endosomally-derived vesicles, known as exosomes. Exosomes contain proteins, messenger RNA (mRNA) and microRNA (miRNA) that play a prominent role in cellular signaling, removal of unwanted proteins, and transfer of cellular pathogens to other cells. Because of their small size, secreted exosomes diffuse into biological fluids (blood, cerebrospinal fluid (CSF) and urine) and circulate in the interstitial space, both in the brain and the periphery. Neuronal exosomes have unique neuron-specific surface markers, which enable targeted examination from circulating biological fluids. We hypothesize that elevations of amyloid-beta (Aβ) peptides and phosphorylated-Tau (P-Tau) in neuronal exosomes may document preclinical AD in those with DS. In a recent manuscript, we demonstrated that neuronal exosome levels of Aβ1-42, P-T181-Tau and P-S396-Tau were significantly elevated in individuals with DS compared to age-matched controls at an early age. These early increases in Aβ1-42, P-T181-Tau, and P- S396-Tau in individuals with DS may provide a basis for early intervention as targeted treatments become available. We wish to continue these preliminary studies by examining AD biomarkers in exosomes in relationship to cognitive impairment and CSF biomarkers in participants with DS (Aim 1). Further, Tau protein aggregates into neurofibrillary tangles (NFTs) that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded Tau propagating through the brain seeds neurotoxic aggregation of soluble Tau in recipient neurons. In Aim 2 of this application, we will perform seeding experiments using exosomes from patients with DS and DS-AD injected into the brain of a DS mouse model, to determine seeding capacity of Tau species produced in the brain of those with DS. These studies will lead to more information regarding validity of exosome biomarkers to predict conversion to dementia in DS, and will also provide novel information regarding mechanistic effects of toxic Tau species in the DS brain.

抽象的唐氏综合症（DS）是人类中最常见的非致死性非整倍性，由完整或部分引起 21染色体三体。除了智力残疾和非典型发展外，还经常在DS中观察到痴呆症的患病率明显高，发病率早于一般人群。一个强候选机制是位于上面的淀粉样蛋白β前体蛋白（APP）基因染色体21染色体，在患有DS的人中三倍，在很小的时候就引起有毒的淀粉样蛋白肽。患有DS的个体表现出阿尔茨海默氏病（AD）神经病理学和痴呆症的早期。存在年轻人患有DS的AD病理学相对未知，部分原因是脑组织的缺乏可在早期时期学习。因此，反映早期AD病理的生物标志物是由于神经保护疗法最终将针对DS的年轻人，因此很大的兴趣。最多人体中的细胞类型，包括神经元，释放出小的内体衍生蔬菜，称为外泌体。外泌体包含蛋白质，信使RNA（mRNA）和microRNA（miRNA），它们在细胞信号传导，去除不良蛋白质以及将细胞病原体转移到其他细胞。由于它们的小尺寸，分泌的外泌体扩散成生物液（血液，脑脊液（CSF）和尿液）和在大脑和外围的间质空间中圆圈。神经元外泌体具有独特的神经特异性的表面标记，可以通过循环生物流体进行靶向检查。我们假设神经元中淀粉样蛋白β（Aβ）肽和磷酸化TAU（p-TAU）的升高外泌体可以记录DS患者中的临床前广告。在最近的手稿中，我们证明了患有Aβ1-42，P-T181-TAU和P-S396-TAU的神经元外泌体水平在患有与年龄匹配的对照相比，DS。这些早期在Aβ1-42，P-T181-TAU和P-中增加了 DS的个体中的S396-TAU可能会在有针对性的治疗中为早期干预提供基础可用的。我们希望通过检查外泌体中的AD生物标志物来继续这些初步研究与DS参与者的认知障碍和CSF生物标志物的关系（AIM 1）。此外，tau蛋白聚集成神经原纤维缠结（NFTS），逐渐扩散到突触连接的大脑地区。已经提出了一种类似prion的机制：通过脑种子传播错误的tau 受体神经元中固体TAU的神经毒性聚集。在此应用程序的AIM 2中，我们将执行使用来自DS和DS-AD患者注入DS小鼠大脑的患者的外泌体的播种实验模型，确定DS患者大脑中产生的Tau物种的播种能力。这些研究会导致有关外泌体生物标志物有效性的更多信息，以预测ds中痴呆的转化，并将提供有关DS脑中有毒tau物种的机械作用的新信息。