Tate B, Aboody-Guterman K S, Morris A M, Walcott E C, Majocha R E, Marotta C A
Department of Psychiatry, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7090-4. doi: 10.1073/pnas.89.15.7090.
Alzheimer disease patients exhibit irregularities in the patterns of normally circadian (daily) rhythms. Alzheimer-type pathology has been reported in the hypothalamus and in the suprachiasmatic nuclei, the putative site of the circadian oscillator. We examined the relationship between the neuropathology of Alzheimer disease, as modeled by an animal system, and circadian dysregulation by grafting genetically transformed cells that overexpress beta/A4 amyloid into the suprachiasmatic nuclei of adult rats. Grafts of beta/A4-positive cells, but not of control cells, significantly altered the pattern of activity of implanted rats. Although experimental conditions included light-dark cycles that normally tend to drive rats to 24-h rhythms, animals with grafts of beta/A4-positive cells showed abnormally high levels of activity during the light phase in addition to a disrupted circadian pattern. Periodogram analysis demonstrated significant rhythms outside of a circadian range. The body temperature rhythm of these animals was also weak 6 weeks after grafting; however, unlike activity patterns, body temperature regained a circadian period by 8 weeks after cell implantation. These data indicate that disruption of circadian activity is a behavioral measure of the consequences of beta/A4 accumulation in brain implants.
阿尔茨海默病患者的正常昼夜节律模式出现异常。下丘脑和视交叉上核（昼夜节律振荡器的假定部位）已报道有阿尔茨海默型病理改变。我们通过将过表达β/A4淀粉样蛋白的基因转化细胞移植到成年大鼠的视交叉上核，研究了以动物系统为模型的阿尔茨海默病神经病理学与昼夜节律失调之间的关系。移植β/A4阳性细胞而非对照细胞，显著改变了植入大鼠的活动模式。尽管实验条件包括通常会使大鼠趋向于24小时节律的明暗循环，但移植了β/A4阳性细胞的动物除了昼夜节律模式紊乱外，在光照期还表现出异常高的活动水平。周期图分析显示在昼夜节律范围之外有显著节律。这些动物在移植6周后体温节律也较弱；然而，与活动模式不同，细胞植入8周后体温恢复了昼夜周期。这些数据表明，昼夜活动的破坏是脑植入物中β/A4积累后果的一种行为指标。
