Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
J Chem Neuroanat. 2011 Oct;42(2):111-7. doi: 10.1016/j.jchemneu.2011.02.004. Epub 2011 Mar 17.
The higher incidence rate of Alzheimer's disease (AD) in elderly women indicates that gender plays a role in AD pathogenesis. Evidence from clinical and pharmacologic studies, neuropathological examinations, and models of hormone replacement therapy suggest that cholinergic basal forebrain (CBF) cortical projection neurons within the nucleus basalis (NB), which mediate memory and attention and degenerate in AD, may be preferentially vulnerable in elderly women compared to men. CBF neurons depend on nerve growth factor (NGF) and their cognate receptors (trkA and p75(NTR)) for their survival and maintenance. We recently demonstrated a shift in the balance of NGF and its receptors toward cell death mechanisms during the progression of AD. To address whether gender affects NGF signaling system expression within the CBF, we used single cell RNA amplification and custom microarray technologies to compare gene expression profiles of single cholinergic NB neurons in tissue specimens from male and female members of the Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. p75(NTR) expression within male cholinergic NB neurons was unchanged across clinical diagnosis, whereas p75(NTR) mRNA levels in female NB neurons exhibited a ∼40% reduction in AD compared to NCI. Male AD subjects displayed a ∼45% reduction in trkA mRNA levels within NB neurons compared to NCI and MCI. In contrast, NB neuronal trkA expression in females was reduced ∼50% in both MCI and AD compared to NCI. Reduced trkA mRNA levels were associated with poorer global cognitive performance and higher Braak scores in the female subjects. In addition, we found a female-selective reduction in GluR2 AMPA glutamate receptor subunit expression in NB neurons in AD. These data suggest that cholinergic NB neurons in females may be at greater risk for degeneration during the progression of AD and support the concept of gender-specific therapeutic interventions during the preclinical stages of the disease.
阿尔茨海默病（AD）在老年女性中的发病率较高，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激素替代疗法模型的证据表明，基底核（NB）内介导记忆和注意力的胆碱能基底前脑（CBF）皮质投射神经元在 AD 中退化，与男性相比，老年女性可能更容易受到影响。CBF 神经元依赖神经生长因子（NGF）及其同源受体（trkA 和 p75（NTR））存活和维持。我们最近证明，在 AD 进展过程中，NGF 及其受体的平衡向细胞死亡机制发生转变。为了确定性别是否影响 CBF 中的 NGF 信号系统表达，我们使用单细胞 RNA 扩增和定制微阵列技术比较了来自宗教秩序研究的男性和女性组织标本中单一胆碱能 NB 神经元的基因表达谱，这些人死于无认知障碍（NCI）、轻度认知障碍（MCI）或轻度/中度 AD 的临床诊断。男性胆碱能 NB 神经元内 p75（NTR）的表达在整个临床诊断过程中保持不变，而女性 NB 神经元中的 p75（NTR）mRNA 水平在 AD 中与 NCI 相比降低了约 40%。与 NCI 和 MCI 相比，男性 AD 受试者的 NB 神经元中的 trkA mRNA 水平降低了约 45%。相比之下，与 NCI 相比，MCI 和 AD 中女性 NB 神经元的 trkA 表达分别降低了约 50%。trkA mRNA 水平降低与女性受试者的整体认知表现较差和 Braak 评分较高相关。此外，我们发现 AD 中 NB 神经元中的 GluR2 AMPA 谷氨酸受体亚基表达存在女性选择性降低。这些数据表明，女性的胆碱能 NB 神经元在 AD 进展过程中可能更容易退化，并支持在疾病的临床前阶段进行针对性别特异性的治疗干预的概念。
