Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function
Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function
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DOI：
10.1006/exnr.1998.6789
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发表时间：
1998-06-01
影响因子：
5.3
通讯作者：
Gibbs, RB
中科院分区：
文献类型：
--
作者：
Gibbs, RB
最近的研究表明，女性比男性患阿尔茨海默病的风险更大，雌激素替代可以帮助降低绝经后妇女患阿尔茨海默病相关痴呆的风险和严重程度。我们假设患阿尔茨海默氏症相关痴呆的风险增加部分是由于绝经后妇女卵巢功能的丧失以及卵巢激素水平降低对基础前脑胆碱能功能的影响。在本研究中，我们研究了衰老和卵巢切除对大鼠基底前脑胆碱能神经元的影响，以确定(1)衰老对雄性和雌性基底前脑胆碱能神经元的影响是否存在差异；(2)卵巢功能的长期丧失是否会导致基底前脑胆碱能功能的缺陷，而不是与年龄和性别相关的缺陷。在第一部分研究中，我们分别在13、19和25月龄时处死性腺完整的雄性和雌性大鼠，比较衰老对大细胞基底核（NBM）和中隔（MS）胆碱能神经元的影响。在研究的第二部分中，雌性大鼠在13个月大时切除卵巢，然后在3个月和6个月后与性腺完整、年龄匹配的对照组一起被处死。通过MS和NBM处理相邻切片，进行免疫细胞化学检测胆碱乙酰转移酶（ChAT）和p75ntr样免疫反应性，或进行ChAT和trkA mRNA的原位杂交检测和定量。第一部分的结果显示，年龄对性腺完整动物MS和NBM中胆碱能神经元的相对大小和密度没有显著影响。同样，对表达p75NTR蛋白的胆碱能神经元的相对数量没有显著影响。然而，在13至25月龄之间，在性腺完整的雌性MS中检测到trkA mRNA的显著减少，而在雄性MS中则没有。衰老对ChAT mRNA无显著影响。第二部分的结果显示，与年龄匹配、性腺完整的对照组相比，卵巢切除术后6个月（而不是3个月）雌性大鼠的MS和NBM中ChAT和trkA mRNA均显著降低。短期雌激素替代在卵巢切除术后6个月开始，并在牺牲前3天给予，部分恢复MS中ChAT mRNA水平和NBM中trkA mRNA水平。这些发现提示卵巢激素在维持MS和NBM中ChAT和trkA的正常表达水平中发挥作用。卵巢切除术后6个月，MS和NBM中ChAT mRNA的减少表明，卵巢功能的长期丧失导致基底前脑投射到海马和皮质的胆碱能神经元功能状态下降。此外，我们假设在MS中检测到trkA mRNA的减少是衰老的结果，在MS和NBM中检测到trkA mRNA的减少是卵巢切除术的反应，反映了高亲和力神经生长因子（NGF）受体产生的减少，以及胆碱能神经元对内源性NGF的反应性降低。反过来，这可能增加胆碱能神经元对衰老和疾病影响的易感性，从而导致基底前脑胆碱能下降。我们得出结论，卵巢功能的长期丧失和衰老对基底前脑胆碱能神经元有负面影响。这些影响可能会增加绝经后妇女与衰老和阿尔茨海默病相关的认知能力下降的风险和严重程度。(C) 1998学术出版社。
Recent studies suggest that women are at greater risk for Alzheimer's disease than men and that estrogen replacement can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that the increased risk for Alzheimer's-related dementia is due, in part, to the loss of ovarian function in postmenopausal women and to the effects that decreased levels of ovarian hormones have on basal forebrain cholinergic function. In the present study, the effects of aging and ovariectomy on cholinergic neurons in the rat basal forebrain were examined to determine (1) whether aging differentially affects cholinergic neurons in the basal forebrain of males vs females, and (2) whether long-term loss of ovarian function produces deficits in basal forebrain cholinergic function beyond those associated with aging and sex. In part I of the study, gonadally intact male and female rats were sacrificed at 13, 19, and 25 months of age and the effects of aging on cholinergic neurons in the medial septum (MS) and nucleus basalis magnocellularis (NBM) were compared. In part II of the study, female rats were ovariectomized at 13 months of age and then sacrificed 3 and 6 months later along with gonadally intact, age-matched controls. Adjacent sections through the MS and NBM were processed for either immunocytochemical detection of choline acetyltransferase (ChAT) and p75NTR-Like immunoreactivity or for in situ hybridization detection and quantification of ChAT and trkA mRNA. Results from part I revealed no significant effects of age on the relative size or density of cholinergic neurons in the MS and NBM of gonadally intact animals. Likewise, no significant effects on the relative numbers of cholinergic neurons expressing p75NTR protein were detected. However, a significant decrease in trkA mRNA was detected in the MS of gonadally intact females, but not males, between 13 and 25 months of age. No significant effects of aging on ChAT mRNA were detected. Results from part II revealed significant decreases in both ChAT and trkA mRNA in the MS and NBM of female rats sacrificed 6 months, but not 3 months, following ovariectomy relative to age-matched, gonadally intact controls. Short-term estrogen replacement initiated 6 months following ovariectomy and administered for 3 days prior to sacrifice partially restored ChAT mRNA levels in the MS and trkA mRNA levels in the NBM.These findings suggest that ovarian hormones play a role in maintaining normal levels of ChAT and trkA expression in the MS and NBM. The fact that ChAT mRNA was decreased in the MS and NBM at 6 months following ovariectomy suggests that long-term loss of ovarian function produces a decrease in the functional status of basal forebrain cholinergic neurons projecting to the hippocampus and cortex. In addition, we hypothesize that the decreases in trkA mRNA detected both in the MS as a function of aging, and in the MS and NBM in response to ovariectomy, reflect decreases in the production of high affinity nerve growth factor (NGF) receptors, and a decrease in the responsiveness of the cholinergic neurons to endogenous NGF. This, in turn, may increase the susceptibility of the cholinergic neurons to the effects of aging and disease and thereby contribute to basal forebrain cholinergic decline. We conclude that long-term loss of ovarian function combined with aging has a negative impact on basal forebrain cholinergic neurons. These effects may contribute to the risk and severity of cognitive decline associated with aging and Alzheimer's disease in postmenopausal women. (C) 1998 Academic Press.