Gender differences in cholinergic molecular pathology in Alzheimer's disease

描述（申请人提供）：老年女性阿尔茨海默病（Alzheimer's disease， AD）发病率较高，说明性别在AD发病机制中起一定作用。来自临床和药理学研究、神经病理学检查、更年期和性激素替代模型的几条证据表明，与男性相比，老年女性的胆碱能基底前脑（CBF）投射系统可能更容易受到退行性疾病的影响，该系统介导AD患者的记忆和注意力过程并发生退化。为了支持这一假设，我们有有趣的试点数据表明，与患有NCI的男性相比，无认知障碍（NCI）的女性CBF基底核（NB）皮质投射神经元的数量可能减少。此外，单个胆碱能NB神经元的初步基因表达谱研究表明，与诊断为轻度认知障碍（MCI）的男性受试者相比，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神经元依赖于NGF存活，这些数据表明，在认知衰退的早期阶段，女性的NB皮质投射神经元比男性更容易受到伤害。为了探索脑卒中在阿尔茨海默病性别特异性机制中的潜在参与，我们将首先采用无偏倚的体视学方法来测试在阿尔茨海默病的进展过程中，与男性相比，女性胆碱能NB神经元的细胞丢失、萎缩和表型改变更大。本研究的组织切片将从临床诊断为死前NCI、遗忘性MCI（一种假定的临床前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，以测试在疾病进展过程中，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）的水平是否相对于男性发生改变。综上所述，这些研究将探索阿尔茨海默病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。公共卫生相关性：阿尔茨海默病研究越来越关注识别神经生物学风险因素，以应对迫在眉睫的危机，因为“婴儿潮”一代达到了患该疾病风险最高的年龄。由于女性性别是阿尔茨海默病的危险因素，因此必须开展新的研究，以探索阿尔茨海默病中性别差异的分子病理学。目前的建议探讨是否脑胆碱能系统潜在的记忆和注意力是选择性地更容易受到老年女性比男性阿尔茨海默病变性。

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.