APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD

转基因小鼠、家族性和散发性 AD 中的 APP/AB/Tau 生物化学

• 批准号: 8463071
• 负责人: ALEX E ROHER
• 金额: $ 32.21万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463071
• 关键词: AD transgenic mice; Accounting; Active Immunization; Affect; Affinity; Age; Age of Onset; Age-Years; Alzheimer' s Disease; Alzheimer' s disease model; American; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Asses; Biochemical; Biochemistry; Bioinformatics; Biological Models; Brain; Cerebrum; Chemicals; Chemistry; Cleaved cell; Clinical; Clinical Trials; Databases; Dementia; Deposition; Detection; Development; Diagnostic; Disease; Elderly; Employee Strikes; Engineering; Enzymes; Evaluation; Exhibits; Functional disorder; Future; Genes; Genetic; Goals; Histology; Human; Human Characteristics; Immunization; Immunoassay; Immunotherapy; Individual; Intervention; Knowledge; Mass Spectrum Analysis; Membrane; Membrane Microdomains; Metabolic; Microtubule Proteins; Mitochondria; Molecular; Mouse Protein; Mus; Mutation; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Organelles; Outcome; Passive Immunization; Pathogenesis; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Plasma; Presenile Alzheimer Dementia; Process; Protein Precursors; Protein Sequence Analysis; Protocols documentation; Quality of life; Role; Route; Senile Plaques; Techniques; Testing; Tg2576; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transgenes; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Western Blotting; alpha synuclein; base; beta-site APP cleaving enzyme 1; case control; cost; density; design; efficacy testing; familial Alzheimer disease; gray matter; mitochondrial membrane; molecular phenotype; mouse model; next generation; novel; presenilin; presenilin-1; presenilin-2; prevent; public health relevance; response; secretase; success; synuclein; tau Proteins; tau mutation; tool; white matter

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA and this number is projected to quadruple by 2050. This neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of over $100 billion annually. There is an urgent need for effective therapeutic interventions that may prevent, delay the age of onset or relent the course of this dementia. Transgenic (Tg) mice expressing human AD genes such as amyloid-¿ precursor protein (APP), presenilin (PS), the microtubule protein tau, ¿-amyloid cleaving enzyme-1 (BACE-1), and a-synuclein have provided tools to investigate both the pathogenesis and the efficacy of treatments for these neuropathological disorders. Our goal, in Specific Aim 1, is to better understand the strengths and limitations of several Tg mice models by establishing the degree of biochemical similarities and differences between these paradigms and human AD subjects. In Specific Aim 2, soluble and deposited A¿ remaining after anti- A¿ active and passive immunizations of AD patients will be quantitatively and qualitatively assessed in gray and white matter and cerebral vasculature to evaluate the effects of immunization on A¿ dynamics and its clinical impact on the course of AD. In Specific Aim 3, the APP and A¿ peptides retained in the brain microsomal, mitochondrial and lipid raft brain fractions in AD and non-demented controls will be determined to better understand the role of neuronal and glial participation in the pathophysiology of AD. To achieve these three objectives physicochemical techniques involving the use of density and affinity gradients, chaotropic agents, multiple chromatographic separations, amino acid analysis, peptide sequencing, mass spectrometry, bioinformatics data bases, immunoassays and Western blotting will be implemented. The proposed studies will: 1) aid in the accurate interpretation of Tg mouse experimental responses, 2) help to elucidate at the molecular level the direct and indirect effects of anti- A¿ immunization and 3) discover the pathological consequences, beyond soluble A¿ and deposited amyloid, of membrane-retained APP/ A¿ peptides. A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种痴呆症，影响了美国的400万个个人，该数字预计到2050年。到2050年。这一神经退行性疾病罢工在65岁时的4％的人罢工4％，其中多达85岁的年龄超过100亿美元。迫切需要进行有效的治疗干预措施，这可能会阻止，延迟发病年龄或不放松这种痴呆症的过程。表达人AD基因的转基因（TG）小鼠，例如淀粉样蛋白 - 前体蛋白（APP），Presenilin（PS），微管蛋白tau， - - 氨基蛋白裂解酶-1（BACE-1）和A-突触核蛋白提供了用于调查这些Neuropathoction and Neuropation的工具。在特定目标1中，我们的目标是通过建立这些范式和人类广告主体之间的生化相似性和差异的程度来更好地了解几种TG小鼠模型的优势和局限性。在特定的目标2中，在抗A主动和被动免疫抑制后，将在灰色和白质以及脑脉管系统中进行定量评估，并定性地评估AD患者的主动和被动免疫抑制后，并保留了脑抑制对AD的影响，以评估免疫抑制对A动力学对AD动力学的影响及其对广告的临床影响。在特定的目标3中，将确定在AD和非痴呆对照中保留的APP和A肽保留在AD和非痴呆对照中的APPIDE和脂质筏级分数，以更好地了解神经元和神经胶质参与AD的病理生理学的作用。为了实现这三种目标的物理技术，将实施参与使用密度和亲和力梯度的使用，交际剂，多种色谱分离，氨基酸分析，肽测序，质谱，生物信息图数据盆，免疫测定和蛋白质印迹。拟议的研究将：1）有助于对TG小鼠实验反应的准确解释，2）有助于在分子水平上阐明抗免疫的直接和间接作用，3）3）发现固体A检验的病理后果，超出固体A和沉积的淀粉样淀粉样蛋白，对膜上固定的应用App/ A apeptides。对AD分子表型及其临床反应的更全面了解将有助于发现和应用有效的治疗，从而阻止AD或增强AD患者的生活质量。

项目成果

Molecular Differences and Similarities Between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis.

• DOI: 10.4137/bci.s13025
• 发表时间: 2013
• 期刊: Biochemistry insights
• 作者: Maarouf CL;Kokjohn TA;Whiteside CM;Macias MP;Kalback WM;Sabbagh MN;Beach TG;Vassar R;Roher AE
• 通讯作者: Roher AE

Biochemical assessment of precuneus and posterior cingulate gyrus in the context of brain aging and Alzheimer's disease.

• DOI: 10.1371/journal.pone.0105784
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Maarouf CL;Kokjohn TA;Walker DG;Whiteside CM;Kalback WM;Whetzel A;Sue LI;Serrano G;Jacobson SA;Sabbagh MN;Reiman EM;Beach TG;Roher AE
• 通讯作者: Roher AE

Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets.

• DOI: 10.1016/j.bbadis.2011.07.004
• 发表时间: 2011-11
• 期刊: Biochimica et biophysica acta
• 作者: Kokjohn TA;Van Vickle GD;Maarouf CL;Kalback WM;Hunter JM;Daugs ID;Luehrs DC;Lopez J;Brune D;Sue LI;Beach TG;Castaño EM;Roher AE
• 通讯作者: Roher AE

An association with great implications: vascular pathology and Alzheimer disease.

具有重大意义的关联：血管病理学和阿尔茨海默病。

• DOI: 10.1097/01.wad.0000201855.39246.2d
• 发表时间: 2006
• 期刊: Alzheimer disease and associated disorders
• 影响因子: 2.1
• 作者: Roher,AlexE;Kokjohn,TylerA;Beach,ThomasG
• 通讯作者: Beach,ThomasG

Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease.

Presenilin-1 280Glu-->Ala 突变改变 C 端 APP 加工，产生更长的 abeta 肽：对阿尔茨海默病的影响。

• DOI: 10.2119/2007-00094.vanvickle
• 发表时间: 2008
• 期刊: Molecular medicine (Cambridge, Mass.)
• 作者: VanVickle,GregoryD;Esh,CheraL;Kokjohn,TylerA;Patton,RLyle;Kalback,WalterM;Luehrs,DeanC;Beach,ThomasG;Newel,AmandaJ;Lopera,Francisco;Ghetti,Bernardino;Vidal,Ruben;Castaño,EduardoM;Roher,AlexE
• 通讯作者: Roher,AlexE