Gender differences in cholinergic molecular pathology in Alzheimer's disease

阿尔茨海默病胆碱能分子病理学的性别差异

• 批准号: 7666082
• 负责人: Scott E Counts
• 金额: $ 19.13万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666082
• 关键词: Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Atrophic; Attention; Basal Nucleus of Meynert; Brain; Cells; Cholinomimetics; Clinical; Cognition; Cognitive; Cohort Studies; Custom; Data; Dementia; Densitometry; Development; Diagnosis; Disease Progression; Education; Elderly; Elderly woman; Exhibits; Female; Funding; Gender; Gender Role; Gene Expression; Gene Expression Profiling; Generations; Genotype; Gonadal Steroid Hormones; Harvest; Hormonal; Impaired cognition; Incidence; Investigation; Life Style; Longitudinal Studies; Measurement; Measures; Mediating; Memory; Menopause; Messenger RNA; Metabolic; Methods; Modeling; Molecular; Molecular Profiling; NGFR Protein; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurobiology; Neurofibrillary Tangles; Neurons; Occupations; Optics; Pathogenesis; Pathologic; Play; Process; RNA amplification; Relative (related person); Religion and Spirituality; Reproductive History; Research; Risk Factors; Role; Semantic memory; Sex Characteristics; Staging; Study Section; Study Subject; Survival Rate; Symptoms; Synapses; Syndrome; System; Testing; Tissue Sample; Tissues; Transcript; Woman; aged; basal forebrain; basal forebrain cholinergic neurons; cDNA Arrays; cholinergic; cholinergic neuron; design; disorder risk; genetic association; improved; insight; male; men; mild neurocognitive impairment; molecular pathology; neuron loss; novel; pre-clinical; public health relevance; reproductive; sex

DESCRIPTION (provided by applicant): The higher incidence rate of Alzheimer's disease (AD) in elderly women indicates that gender plays a role in AD pathogenesis. Several lines of evidence from clinical and pharmacologic studies, neuropathological examinations, and models of menopause and sex hormone replacement suggest that the cholinergic basal forebrain (CBF) projection system, which mediates memory and attentional processes and degenerates in AD, may be preferentially vulnerable to degenerative processes in elderly women as compared to men. In support of this hypothesis, we have intriguing pilot data suggesting that the number of CBF nucleus basalis (NB) cortical projection neurons in women with no cognitive impairment (NCI) may be reduced compared to men with NCI. In addition, preliminary gene expression profiling studies of single cholinergic NB neurons indicate that nerve growth factor (NGF) receptor mRNA levels are selectively reduced in female subjects relative to male subjects diagnosed with mild cognitive impairment (MCI), a prodromal stage of AD. As CBF neurons depend on NGF for survival, these data suggest that NB cortical projection neurons are selectively vulnerable in women compared to men in the earliest stages of cognitive decline. To explore the potential involvement of the CBF in gender-specific mechanisms of AD, we will first perform unbiased stereological methods to test that there is greater cell loss, atrophy, and phenotypic alteration of cholinergic NB neurons in women compared to men during the progression of AD. Tissue sections for this study will be harvested from subjects clinically diagnosed antemortem with NCI, amnestic MCI (a putative preclinical AD syndrome), or mild AD. Secondly, we will perform single cell gene expression analysis of cholinergic NB neurons from these same cases to test whether levels of NGF receptor and other functional classes of mRNAs (e.g., cytoskeletal, synaptic, metabolic) are altered in female subjects during disease progression relative to males. Taken together, these studies will explore cholinergic mechanisms underlying gender differences in the risk for AD and may identify novel targets for gender-specific therapy. PUBLIC HEALTH RELEVANCE: Alzheimer's disease research has become increasingly focused on identifying neurobiologic risk factors to confront the looming crisis as the "baby boomer" generation reaches the ages at greatest risk for the disease. As female gender is a risk factor for AD, new lines of investigation must be undertaken to explore the molecular pathology of gender differences in AD. The current proposal explores whether the brain cholinergic system underlying memory and attention is selectively more vulnerable to AD degeneration in aged women compared to men.

描述（由申请人提供）：老年妇女中阿尔茨海默氏病（AD）的发病率较高，表明性别在AD发病机理中起作用。来自临床和药理研究，神经病理学检查以及更年期和性激素替代模型的几种证据表明，胆碱能基础前脑（CBF）投影系统介导了在AD中介导的记忆和注意力过程以及AD中的注意力，并且在AD中的变性可能会比男性与男性相比，优先脆弱。为了支持这一假设，我们有有趣的试点数据，表明与NCI男性相比，无认知障碍（NCI）的女性中CBF核（NB）皮质投射神经元的数量可能会减少。此外，单个胆碱能NB神经元的初步基因表达研究研究表明，相对于诊断出患有轻度认知障碍（MCI）的男性受试者，在女性受试者中，神经生长因子（NGF）受体mRNA水平被选择性降低，AD的前途阶段。由于CBF神经元依赖于NGF来生存，因此这些数据表明，与男性相比，在认知能力下降的最早阶段，女性的NB皮质投射神经元有选择地易受伤害。为了探索CBF参与AD性别特异性机制的潜在参与，我们将首先执行无偏见的立体方法，以测试与AD进展过程中女性相比，女性胆碱能NB神经元的细胞丧失，萎缩和表型变化。这项研究的组织切片将从受试者临床诊断为NCI，Amnestic MCI（假定的临床前AD综合征）或轻度AD的受试者中收获。其次，我们将对来自这些情况的胆碱能NB神经元进行单细胞基因表达分析，以测试NGF受体和其他功能性类别的mRNA水平（例如，疾病进展过程中女性受试者的细胞骨架，突触，突触，代谢）是否会改变。综上所述，这些研究将探讨AD风险中性别差异的胆碱能机制，并可能识别出性别特异性治疗的新靶标。公共卫生相关性：阿尔茨海默氏病研究越来越集中于识别神经生物学危险因素，以面对迫在眉睫的危机，因为“婴儿潮一代”一代人的年龄达到了最大的疾病风险。由于女性性别是AD的危险因素，因此必须进行新的调查线，以探索AD中性别差异的分子病理。当前的提案探讨了与男性相比，老年女性的脑胆碱能系统是否有选择地容易受到老年女性变性的影响。