ChAT, AChE, and Cholinergic Neurons in Aging and AD

ChAT、AChE 和胆碱能神经元在衰老和 AD 中的作用

• 批准号: 8072621
• 负责人: STEVEN G YOUNKIN
• 金额: $ 57.84万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072621
• 关键词: APP717; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid; Amyloid Fibrils; Biochemical Markers; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; CCL2 gene; CSF2 gene; Cells; Cholesterol; Chromosomes, Human, Pair 21; Collaborations; Conditioned Culture Media; Consensus; Cultured Cells; Data; Deposition; Diagnostic; Disease; Event; Fostering; Funding; Grant; Heart Diseases; Human; Immunotherapy; Incidence; Individual; Investigation; Laboratories; Link; Maps; Mutation; Pathogenesis; Patients; Peptides; Pharmacologic Substance; Phase; Plasma; Presenile Alzheimer Dementia; Preventive; Process; Protein Precursors; Reporting; Risk; Senile Plaques; Series; Transgenic Organisms; adiponectin; angiogenin; apolipoprotein E-4; cerebral atrophy; cholinergic neuron; early onset; familial Alzheimer disease; hippocampal atrophy; interest; mild neurocognitive impairment; molecular marker; neuropathology; platelet-derived growth factor BB; pre-clinical; presenilin-1; presenilin-2; prevent; programs; protein B; protein aggregate; protein aggregation; therapeutic target; tool; working group

DESCRIPTION (provided by applicant): There is a growing consensus that the best way to manage Alzheimer's Disease (AD) will be through preventive therapy. To facilitate preventive therapy, it is important to develop AD-related biomarkers that can be used to identify at risk individuals in the same way that cholesterol levels are used to identify those at risk for atherosclerotic heart disease. For this reason, we proposed in the last cycle to determine if plasma AB40 and/or AB42 might be useful biomarkers for identifying at risk individuals. In 563 normal subjects that we followed longitudinally, the plasma AB42/40 ratio was an excellent biomarker for identifying those who developed Mild Cognitive Impairment or AD in three to five years. The cumulative incidence of AD/MCI was significantly greater in subjects with an AB42/AB40 ratio in the lowest quartile as compared to those with a ratio in the highest quartile after adjusting for age and ApoE4. Subjects with an ApoE4 allele and a low (below median) AB42/40 ratio, began to develop AD/MCI at 2-3 years and, by 5 years, over 20% of the subjects in this group were affected. In contrast, only 3% of the ApoE 4 carriers with a high (above median) AB42/AB40 ratio developed AD in five years. Combining age and the AB42/AB40 ratio was also highly effective in separating subjects who developed disease from those who did not. Older subjects (age > 80 years) with a low (below median) AB42/40 ratio began to develop AD/MCI at 2-3 years and, by 5 years, over 20% of the subjects in this group were affected. In contrast, less than 4% of all other subjects developed AD within five years. If these findings can be confirmed, it seems likely that the plasma AB42/AB40 ratio can become an important biomarker for developing and implementing a preventive approach to AD therapy. Our specific aims are to (1) confirm that the plasma AB42/AB40 ratio is a useful biomarker for identifying those who will develop MCI or AD in three to five years, and (2) determine if elevated AB (AB40 and/or AB42) is useful for identifying those who will develop MCI or AD in five to fifteen years. Several additional biomarkers will be evaluated in the same longitudinal series where plasma AB is analyzed. Dr. Wyss-Coray will analyze BDNF, AcrpSO (aka adiponectin), angiogenin, PDGF-BB, and MCP-1. Dr. Jack will analyze hippocampal atrophy as well as whole brain atrophy using the Boundary Shift Integral (BSI) approach. The utility of these additional biomarkers will be evaluated singly as compared to plasma Aft and jointly with plasma AB.

描述(由申请人提供)：越来越多的人达成共识，认为管理阿尔茨海默病(AD)的最佳方法将是通过预防性治疗。为了促进预防性治疗，重要的是开发与AD相关的生物标志物，这些生物标志物可以用来识别高危个体，就像用胆固醇水平来识别动脉粥样硬化性心脏病的高危个体一样。出于这个原因，我们在上一个周期中建议确定血浆AB40和/或AB42是否可以作为识别高危个体的有用生物标志物。在我们纵向跟踪的563名正常受试者中，血浆AB42/40比率是一个很好的生物标记物，可以用来识别那些在三到五年内发展为轻度认知障碍或AD的人。在调整了年龄和载脂蛋白E4后，AB42/AB40比值位于最低四分位数的受试者的AD/MCI累积发病率显著高于AB42/AB40比值位于最高四分位数的受试者。ApoE4等位基因和AB42/40比值低(低于中位数)的受试者在2-3岁时开始发生AD/MCI，到5岁时，该组中超过20%的受试者受到影响。相比之下，在AB42/AB40比值较高(高于中位数)的载脂蛋白E 4携带者中，只有3%的人在5年内发生了AD。结合年龄和AB42/AB40比率，也可以非常有效地将患疾病的受试者与没有患病的受试者区分开来。AB42/40比值低(低于中位数)的老年受试者(年龄80岁)在2-3岁时开始发生AD/MCI，到5岁时，该组受试者中超过20%的人受到影响。相比之下，在所有其他受试者中，只有不到4%的人在五年内患上了阿尔茨海默病。如果这些发现得到证实，似乎血浆AB42/AB40比率可能成为开发和实施AD预防治疗方法的重要生物标志物。我们的具体目标是：(1)确定血浆AB42/AB40比值是识别3-5年后发生MCI或AD的有用生物标志物；(2)确定升高的AB(AB40和/或AB42)是否有助于识别5-15年后发生MCI或AD的患者。几个额外的生物标志物将在同一纵向系列中进行评估，在那里对血浆AB进行分析。Wyss-Coray博士将分析BDNF、AcrpSO(又名脂联素)、血管生成素、PDGF-BB和MCP-1。Jack博士将使用边界移位积分(BSI)方法分析海马体萎缩和全脑萎缩。这些额外的生物标志物的效用将单独与血浆AFT进行比较，并与血浆AB联合进行评估。

项目成果

Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.

• DOI: 10.1073/pnas.90.20.9513
• 发表时间: 1993-10
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: A. Wertkin;R. S. TURNERt;Samuel J. Pleasure;Todd E. GOLDEt;Steven G. Younkint;J. Trojanowski;Virginia M.-Y. Lee

Production of amyloid beta protein from normal amyloid beta-protein precursor (beta APP) and the mutated beta APPS linked to familial Alzheimer's disease.

从正常的淀粉样β蛋白前体（βAPP）和与家族性阿尔茨海默氏病相关的突变βAPPS中产生淀粉样β蛋白。

• DOI: 10.1111/j.1749-6632.1993.tb23036.x
• 发表时间: 1993
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Golde,TE;Cai,XD;Shoji,M;Younkin,SG
• 通讯作者: Younkin,SG

Soluble derivatives of the beta amyloid protein precursor of Alzheimer's disease are labeled by antisera to the beta amyloid protein.

阿尔茨海默病的β淀粉样蛋白前体的可溶性衍生物被β淀粉样蛋白的抗血清标记。

• DOI: 10.1016/0006-291x(89)91052-8
• 发表时间: 1989
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Palmert,MR;Siedlak,SL;Podlisny,MB;Greenberg,B;Shelton,ER;Chan,HW;Usiak,M;Selkoe,DJ;Perry,G;Younkin,SG
• 通讯作者: Younkin,SG

Astrocytes in Alzheimer's disease gray matter express alpha 1-antichymotrypsin mRNA.

阿尔茨海默病灰质中的星形胶质细胞表达 α1-抗胰凝乳蛋白酶 mRNA。

• 发表时间: 1989
• 期刊: The American journal of pathology
• 作者: Pasternack,JM;Abraham,CR;VanDyke,BJ;Potter,H;Younkin,SG
• 通讯作者: Younkin,SG

Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.

• DOI: 10.1371/journal.pmed.0020355
• 发表时间: 2005-12
• 期刊: PLoS medicine
• 影响因子: 15.8
• 作者: Jankowsky JL;Slunt HH;Gonzales V;Savonenko AV;Wen JC;Jenkins NA;Copeland NG;Younkin LH;Lester HA;Younkin SG;Borchelt DR
• 通讯作者: Borchelt DR