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。

• 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
• 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' 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

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.

摘要