Morley John E, Farr Susan A, Flood James F
Geriatric Research, Education, and Clinical Center, VA Medical Center, St. Louis, Missouri 63106, USA.
Neurobiol Learn Mem. 2002 Jul;78(1):125-38. doi: 10.1006/nlme.2001.4047.
SAMP8 (senescence-accelerated mouse, P8 strain) mice overproduce amyloid precursor protein and beta-amyloid and have learning and memory deficits. Preliminary data have indicated that overproduction of beta-amyloid plays a role in the pathogenesis of acquisition and retention deficits in SAMP8 mice. In the studies reported here, the authors examined the effects of polyclonal and monoclonal antibodies to beta-amyloid on acquisition and retention in an aversive T-maze testing paradigm when injected intracerebroventricularly (ICV) into 12-month SAMP8/TaJF mice. Both the polyclonal and monoclonal antibodies improved acquisition and retention when injected ICV 1 to 14 days prior to acquisition testing. Injection of all three antibodies intrahippocampally immediately following training improved retention on the T-maze when mice were tested 7 days later. The authors next studied the effect of monoclonal beta-amyloid antibody injected 48 h prior to training on the effect on retention in the T-maze of drugs modulating classical neurotransmitters. Arecoline and glutamate were injected directly into the hippocampus, and ketanserin, methiothepen, bicuculline, and OH-saclofen were injected into the septum. Previously, the authors have found that the doses of these drugs required to improve retention are markedly altered in 12-month SAMP8/TkJF mice compared to 4-month P8 mice. In these studies, it was demonstrated that antibody to beta-amyloid resulted in these drugs improving retention at doses that improved memory in 4-month SAMP8/TaJF mice. Based on these findings, we conclude that beta-amyloid overproduction is at least in part responsible for the acquisition and memory deficits in 12-month-old SAMP8/TaJF mice. Antibody to beta-amyloid restores the retention response to neurotransmitter manipulation to that seen in 4-month-old mice. beta-amyloid appears to play a key role in the loss of acquisition and retention seen in SAMP8/TaJF mice.
SAMP8（衰老加速小鼠，P8品系）小鼠过量产生淀粉样前体蛋白和β-淀粉样蛋白，并存在学习和记忆缺陷。初步数据表明，β-淀粉样蛋白的过量产生在SAMP8小鼠获取和保持缺陷的发病机制中起作用。在本文报道的研究中，作者将β-淀粉样蛋白的多克隆抗体和单克隆抗体脑室内注射（ICV）到12个月大的SAMP8/TaJF小鼠体内，研究其在厌恶性T迷宫测试范式中对获取和保持的影响。在获取测试前1至14天进行ICV注射时，多克隆抗体和单克隆抗体均改善了获取和保持能力。训练后立即海马内注射所有三种抗体，7天后对小鼠进行测试时，改善了T迷宫中的保持能力。作者接下来研究了训练前48小时注射单克隆β-淀粉样蛋白抗体对调节经典神经递质的药物在T迷宫中保持能力的影响。将槟榔碱和谷氨酸直接注射到海马体中，将酮色林、甲硫噻吩、荷包牡丹碱和羟基舒必利注射到隔区。此前，作者发现，与4个月大的P8小鼠相比，12个月大的SAMP8/TkJF小鼠改善保持能力所需的这些药物剂量有显著变化。在这些研究中，证明了β-淀粉样蛋白抗体使这些药物在改善4个月大的SAMP8/TaJF小鼠记忆的剂量下提高了保持能力。基于这些发现，我们得出结论，β-淀粉样蛋白的过量产生至少部分导致了12个月大的SAMP8/TaJF小鼠的获取和记忆缺陷。β-淀粉样蛋白抗体将对神经递质操纵的保持反应恢复到4个月大小鼠的水平。β-淀粉样蛋白似乎在SAMP8/TaJF小鼠出现的获取和保持能力丧失中起关键作用。
