Geula Changiz, Bu Jing, Nagykery Nicholas, Scinto Leonard F M, Chan Jennifer, Joseph Jeffrey, Parker Robert, Wu Chuang-Kuo
Laboratory for Neurodegenerative and Aging Research, Section of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
J Comp Neurol. 2003 Jan 6;455(2):249-59. doi: 10.1002/cne.10475.
Cholinergic neurons of the basal forebrain (BFCN) are selectively vulnerable in neurodegenerative disorders of the elderly, particularly in Alzheimer's disease (AD). We investigated age-related changes in the BFCN that may serve as a substrate for this vulnerability. We report a substantial and selective age-related loss of the calcium binding protein calbindin-D(28K) (CB) from the human BFCN. Unbiased stereological estimation indicated that, in individuals under age 65 years, 72% of the choline acetyltransferase (ChAT)-positive BFCN contained CB immunoreactivity. In individuals over age 65 years, only 28% of the BFCN contained CB immunoreactivity, a dramatic loss of 61%. Similar results were obtained using neuronal counts from matching single- or double-stained sections in a larger cohort. The loss of CB immunoreactivity was neurochemically specific. No age-related changes were observed in the number of ChAT- or low-affinity nerve growth factor receptor (p75(NTR))-immunoreactive profiles. The loss of CB was greatest in very old individuals, in whom a small loss of BFCN was observed. Furthermore, the loss of CB displayed the same pattern as the loss of BFCN in AD and was more substantial in the posterior compared with the anterior BFCN sector, suggesting a role for CB in the selective vulnerability of BFCN in AD. The depletion of CB from the BFCN is likely to deprive these neurons of the capacity to buffer high levels of intracellular Ca(2+) and thus to leave them vulnerable to pathological processes, such as those in neurodegenerative disorders, which can cause increased intracellular Ca(2+), thus leading to their degeneration.
基底前脑胆碱能神经元（BFCN）在老年人神经退行性疾病中具有选择性易损性，尤其是在阿尔茨海默病（AD）中。我们研究了BFCN中与年龄相关的变化，这些变化可能是这种易损性的基础。我们报告了人类BFCN中钙结合蛋白钙结合蛋白-D（28K）（CB）出现大量且选择性的与年龄相关的缺失。无偏倚的立体学估计表明，在65岁以下的个体中，72%的胆碱乙酰转移酶（ChAT）阳性BFCN含有CB免疫反应性。在65岁以上的个体中，只有28%的BFCN含有CB免疫反应性，显著损失了61%。在一个更大的队列中，使用匹配的单染或双染切片的神经元计数也得到了类似的结果。CB免疫反应性的丧失在神经化学上具有特异性。未观察到ChAT或低亲和力神经生长因子受体（p75（NTR））免疫反应性轮廓数量与年龄相关的变化。CB的丧失在非常年老的个体中最为明显，在这些个体中观察到BFCN有少量损失。此外，CB的丧失与AD中BFCN的丧失模式相同，并且在后侧BFCN区域比前侧更明显，这表明CB在AD中BFCN的选择性易损性中起作用。BFCN中CB的耗尽可能使这些神经元丧失缓冲高水平细胞内Ca（2+）的能力，从而使它们易受病理过程的影响，例如神经退行性疾病中的病理过程，这些病理过程可导致细胞内Ca（2+）增加，进而导致它们的退化。
