Ishunina Tatjana A, Swaab Dick F
Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
Exp Neurol. 2003 Sep;183(1):159-72. doi: 10.1016/s0014-4886(03)00138-9.
Changes in the interaction between sex hormones and the cholinergic system are presumed to play a role in cognitive decline in aging and Alzheimer's disease (AD). The hippocampus is one of the most strongly affected brain structures in AD and the vertical limb of the diagonal band of Broca (VDB) is its major source of innervation. In the present study we found, surprisingly, for the first time that the neuronal metabolic activity as measured by the size of the Golgi apparatus in the VDB gradually increases after the age of 50 years in controls and that this process starts earlier and is more pronounced in Alzheimer's disease patients. Neuronal metabolic activity in the VDB was significantly higher in AD than in control patients younger than 70 years of age and was higher in control patients over 70 years than in control patients younger than 70 years of age. The activation of VDB neurons during aging was accompanied by an increased nuclear estrogen receptor (ER) beta staining, which was stronger in patients over 70 years of age than in younger subjects (in both controls and AD patients). Interestingly, as in the nucleus basalis of Meynert, nuclear ERalpha expression was markedly enhanced in AD patients compared to controls independent of age. In addition, evidence was found for the influence of APOE genotype on ERalpha and ERbeta staining in the human VDB in aging and in AD. APOE genotype was positively correlated (epsilon 2 < epsilon 3 < epsilon 4) with the percentage of cytoplasm ERalpha-positive VDB neurons in elderly control male and female subjects and with both nuclear and cytoplasm ERbeta-positive neurons in control women. In conclusion, the VDB is compensatory activated and shows more nuclear ER expression in aging and AD in a sex- and APOE genotype-dependent way. So neither global degeneration or a strongly decreased neuronal metabolism nor a lack of sex hormone receptors in the VDB seems to contribute to the decline in cognition in aging or AD in which the hippocampus plays such a crucial role.
性激素与胆碱能系统之间相互作用的变化被认为在衰老和阿尔茨海默病（AD）的认知衰退中起作用。海马体是AD中受影响最严重的脑结构之一，而布罗卡斜角带垂直支（VDB）是其主要的神经支配来源。在本研究中，我们首次令人惊讶地发现，通过VDB中高尔基体大小测量的神经元代谢活性在50岁以后的对照组中逐渐增加，并且这个过程在AD患者中开始得更早且更明显。VDB中的神经元代谢活性在AD患者中显著高于70岁以下的对照患者，并且在70岁以上的对照患者中高于70岁以下的对照患者。衰老过程中VDB神经元的激活伴随着核雌激素受体（ER）β染色增加，70岁以上患者的这种染色比年轻受试者更强（在对照组和AD患者中均如此）。有趣的是，与Meynert基底核一样，AD患者的核ERα表达与对照组相比明显增强，与年龄无关。此外，发现有证据表明APOE基因型对衰老和AD中人类VDB的ERα和ERβ染色有影响。APOE基因型与老年对照男性和女性受试者中细胞质ERα阳性VDB神经元的百分比呈正相关（ε2 < ε3 < ε4），并且与对照女性中核和细胞质ERβ阳性神经元均呈正相关。总之，VDB以性别和APOE基因型依赖的方式在衰老和AD中被代偿性激活并显示出更多的核ER表达。因此，VDB中既没有整体退化或神经元代谢的强烈下降，也没有性激素受体的缺乏，似乎都不会导致在海马体起关键作用的衰老或AD中的认知衰退。
