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(申请人提供)：阿尔茨海默病(AD)是一种痴呆症，在美国有400万老年人患有，预计到2050年这一数字将翻两番。这种神经退行性疾病在65岁的人中有4%的人会受到影响，在85岁的人中有多达40%的人会受到影响，每年的损失超过1000亿美元。迫切需要有效的治疗干预措施，以预防、推迟发病年龄或缓解这种痴呆的病程。表达人类AD基因的转基因(TG)小鼠，如淀粉样前体蛋白(APP)、早老素(PS)、微管蛋白tau、β-淀粉样裂解酶-1(BACE-1)和α-突触核蛋白，为研究这些神经病理疾病的发病机制和治疗效果提供了工具。在具体目标1中，我们的目标是通过建立这些范例与人类AD受试者之间的生化相似和差异程度，更好地了解几种TG小鼠模型的优点和局限性。在特定目标2中，对AD患者抗A主动免疫和被动免疫后残留的可溶性和沉淀性A进行灰质、白质和脑血管的定量和定性评价，以评价免疫对A动力学的影响及其对AD病程的临床影响。在特定的目标3中，将测定AD和非痴呆对照组的脑微粒体、线粒体和脂筏脑部分中保留的APP和A肽，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。为了实现这三个目标，将采用涉及密度和亲和力梯度、共振剂、多层析分离、氨基酸分析、肽序列、质谱学、生物信息学数据库、免疫分析和Western blotting的物理化学技术。建议的研究将有助于：1)帮助准确解释TG小鼠的实验反应，2)有助于在分子水平上阐明抗-A免疫的直接和间接影响，以及3)发现膜保留的APP/A‘多肽的病理后果，而不仅仅是可溶性A和沉积的淀粉样蛋白。更全面地了解AD的分子表型及其临床反应将有助于发现和应用有效的治疗方法来预防AD或提高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

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

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

Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer's disease.

• DOI: 10.3233/jad-2011-110608
• 发表时间: 2011
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Hunter JM;Bowers WJ;Maarouf CL;Mastrangelo MA;Daugs ID;Kokjohn TA;Kalback WM;Luehrs DC;Valla J;Beach TG;Roher AE
• 通讯作者: Roher AE