Early Long-Term Memory Impairment and Changes in the Expression of Synaptic Plasticity-Associated Genes, in the McGill-R-Thy1-APP Rat Model of Alzheimer's-Like Brain Amyloidosis.
Early Long-Term Memory Impairment and Changes in the Expression of Synaptic Plasticity-Associated Genes, in the McGill-R-Thy1-APP Rat Model of Alzheimer's-Like Brain Amyloidosis.
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早期的长期记忆障碍和突触可塑性相关基因表达的变化，在阿尔茨海默氏症的McGill-R-thy1-App大鼠模型中，类似于阿尔茨海默氏症的脑淀粉样变性。
DOI：
10.3389/fnagi.2020.585873
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发表时间：
2020
影响因子：
4.8
通讯作者：
Jerusalinsky DA
中科院分区：
文献类型：
--
作者：
Habif M;Do Carmo S;Báez MV;Colettis NC;Cercato MC;Salas DA;Acutain MF;Sister CL;Berkowicz VL;Canal MP;González Garello T;Cuello AC;Jerusalinsky DA
越来越多的证据支持这一假设，即早期阿尔茨海默病 (AD) 的记忆缺陷可能是由于细胞内淀粉样蛋白 β (Aβ) 寡聚体积累然后分泌到细胞外介质引起的突触衰竭所致。转基因小鼠 AD 模型提供了有关 AD 病理学的宝贵信息。然而，未能将这些发现转化为人类，需要更好地概括人类病理学的模型。 McGill-R-Thy1-APP 转基因 (Tg) 大鼠表达具有瑞典和印第安纳突变（家族性 AD）的人类淀粉样前体蛋白 (APP751)，导致类似 AD 的缓慢进展的脑部淀粉样蛋白病理。因此，它提供了一个独特的机会来研究 AD 早期阶段的学习和记忆能力，此时 Aβ 积累仅限于细胞内区室，在斑块沉积之前。我们的目标是进一步研究 McGill-R-Thy1-APP 杂合子 (Tg+/–) 大鼠的早期记忆缺陷，特别是长期记忆。对开放环境的短期和长期习惯在 3、4 和 6 个月大时得以保留 (Tg+/–)。然而，4个月大（Tg+/–）雄性大鼠的抑制性避免足部电击、新物体识别和社交接近行为的长期记忆严重受损，这表明它们无法巩固和/或唤起此类带有厌恶、情绪和空间成分的联想和辨别记忆。长期记忆缺陷伴随着海马突触可塑性、学习和记忆处理相关基因转录水平的增加，例如 Grin2b、Dlg4、Camk2b 和 Syn1。我们的研究结果表明，除了先前有据可查的学习和记忆缺陷之外，McGill-R-Thy1-APP 大鼠在病理学斑块前的早期阶段还表现出特殊的长期记忆缺陷和深层社会行为改变。这凸显了 Aβ 寡聚物的重要性，并强调了该模型研究 AD 样早期过程的有效性，具有潜在的预测价值。
Accruing evidence supports the hypothesis that memory deficits in early Alzheimer Disease (AD) might be due to synaptic failure caused by accumulation of intracellular amyloid beta (Aβ) oligomers, then secreted to the extracellular media. Transgenic mouse AD models provide valuable information on AD pathology. However, the failure to translate these findings to humans calls for models that better recapitulate the human pathology. McGill-R-Thy1-APP transgenic (Tg) rat expresses the human amyloid precursor protein (APP751) with the Swedish and Indiana mutations (of familial AD), leading to an AD-like slow-progressing brain amyloid pathology. Therefore, it offers a unique opportunity to investigate learning and memory abilities at early stages of AD, when Aβ accumulation is restricted to the intracellular compartment, prior to plaque deposition. Our goal was to further investigate early deficits in memory, particularly long-term memory in McGill-R-Thy1-APP heterozygous (Tg+/–) rats. Short-term- and long-term habituation to an open field were preserved in 3-, 4-, and 6-month-old (Tg+/–). However, long-term memory of inhibitory avoidance to a foot-shock, novel object-recognition and social approaching behavior were seriously impaired in 4-month-old (Tg+/–) male rats, suggesting that they are unable to either consolidate and/or evoke such associative and discriminative memories with aversive, emotional and spatial components. The long-term memory deficits were accompanied by increased transcript levels of genes relevant to synaptic plasticity, learning and memory processing in the hippocampus, such as Grin2b, Dlg4, Camk2b, and Syn1. Our findings indicate that in addition to the previously well-documented deficits in learning and memory, McGill-R-Thy1-APP rats display particular long-term-memory deficits and deep social behavior alterations at pre-plaque early stages of the pathology. This highlights the importance of Aβ oligomers and emphasizes the validity of the model to study AD-like early processes, with potentially predictive value.
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影响因子：
3.7
作者：
Davis KE;Fox S;Gigg J
通讯作者：
Gigg J
影响因子：
15.1
作者：
Do Carmo S;Cuello AC
通讯作者：
Cuello AC
DOI：
10.1073/pnas.1517045112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Chen, Xiaobing;Levy, Jonathan M.;Reese, Thomas S.
通讯作者：
Reese, Thomas S.
影响因子：
4.2
作者：
Berchtold NC;Sabbagh MN;Beach TG;Kim RC;Cribbs DH;Cotman CW
通讯作者：
Cotman CW
影响因子：
2.5
作者：
Bell, KFS;de Kort, GJL;Cuello, AC
通讯作者：
Cuello, AC