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: 7531531
• 负责人: Scott E Counts
• 金额: $ 15.94万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531531
• 关键词: Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Atrophic; Attention; Basal Nucleus of Meynert; Brain; Cells; Cholinergic Agents; Cholinomimetics; Class; Clinical; Cognition; Cognitive; Cohort Studies; Count; 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; Numbers; Occupations; Optics; Pathogenesis; Pathologic; Play; Process; Public Health; RNA amplification; Rate; Relative (related person); Religion and Spirituality; Reproductive History; Research; Risk Factors; Role; Score; 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; 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（申请人提供）：老年女性阿尔茨海默病（AD）的发病率较高，表明性别在 AD 发病机制中发挥着重要作用。来自临床和药理学研究、神经病理学检查以及更年期和性激素替代模型的多项证据表明，与男性相比，介导记忆和注意力过程并在 AD 中退化的胆碱能基底前脑 (CBF) 投射系统可能更容易受到老年女性退化过程的影响。为了支持这一假设，我们有有趣的试验数据表明，与患有 NCI 的男性相比，没有认知障碍 (NCI) 的女性的 CBF 基底核 (NB) 皮质投射神经元的数量可能会减少。此外，对单个胆碱能 NB 神经元的初步基因表达谱研究表明，相对于被诊断患有轻度认知障碍 (MCI)（AD 的前驱阶段）的男性受试者，女性受试者的神经生长因子 (NGF) 受体 mRNA 水平选择性降低。由于 CBF 神经元依赖 NGF 生存，这些数据表明，在认知衰退的早期阶段，与男性相比，女性 NB 皮质投射神经元选择性脆弱。为了探索 CBF 在 AD 性别特异性机制中的潜在参与，我们将首先采用无偏的体视学方法来测试在 AD 进展过程中，与男性相比，女性胆碱能 NB 神经元有更大的细胞损失、萎缩和表型改变。本研究的组织切片将从生前临床诊断为 NCI、遗忘性 MCI（一种推定的临床前 AD 综合征）或轻度 AD 的受试者身上采集。其次，我们将对这些相同病例的胆碱能 NB 神经元进行单细胞基因表达分析，以测试女性受试者的 NGF 受体和其他功能类别的 mRNA（例如细胞骨架、突触、代谢）水平在疾病进展期间相对于男性是否发生改变。总而言之，这些研究将探讨 AD 风险性别差异背后的胆碱能机制，并可能确定性别特异性治疗的新靶点。公共健康相关性：随着“婴儿潮一代”达到了患病风险最高的年龄，阿尔茨海默氏病的研究越来越集中于识别神经生物学危险因素，以应对迫在眉睫的危机。由于女性是 AD 的危险因素，因此必须进行新的研究来探索 AD 性别差异的分子病理学。目前的提案探讨了与男性相比，老年女性的记忆和注意力基础的大脑胆碱能系统是否更容易受到 AD 退化的影响。