Gender differences in cholinergic molecular pathology in Alzheimer's disease

描述（申请人提供）：老年女性中阿尔茨海默病（AD）的发病率较高，表明性别在AD发病机制中起作用。来自临床和药理学研究、神经病理学检查以及绝经和性激素替代模型的几条证据表明，与男性相比，在老年女性中，胆碱能基底前脑（CBF）投射系统（其介导记忆和注意力过程并在AD中退化）可能优先易受退化过程的影响。为了支持这一假设，我们有有趣的试点数据表明，CBF基底核（NB）皮质投射神经元的数量在女性无认知障碍（NCI）可能会减少与男性NCI相比。此外，单个胆碱能NB神经元的初步基因表达谱研究表明，相对于诊断为轻度认知障碍（MCI）（AD的前驱期）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神经元依赖于NGF生存，这些数据表明，NB皮质投射神经元在女性中选择性脆弱，而在认知能力下降的最早阶段，男性。为了探索脑血流在AD性别特异性机制中的潜在参与，我们将首先进行无偏倚的体视学方法来测试，在AD进展过程中，与男性相比，女性中胆碱能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NCI、遗忘型MCI（一种推定的临床前AD综合征）或轻度AD的受试者中采集。其次，我们将对来自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NGF受体和其他功能类别的mRNA（例如，细胞骨架、突触、代谢）相对于男性在疾病进展期间在女性受试者中改变。总之，这些研究将探索AD风险性别差异的胆碱能机制，并可能确定性别特异性治疗的新靶点。公共卫生相关性：随着“婴儿潮”一代达到患阿尔茨海默病风险最大的年龄，阿尔茨海默病的研究越来越集中于确定神经生物学风险因素，以应对迫在眉睫的危机。由于女性是AD的一个危险因素，因此必须进行新的研究以探索AD性别差异的分子病理学。目前的提案探讨了与男性相比，老年女性记忆和注意力相关的脑胆碱能系统是否更容易受到AD变性的影响。

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.