Research Progress in Animal Model of Alzheimer's Disease

doi:10.12300/j.issn.1674-5817.2021.122

Abstract

Abstract:

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, which seriously affects the health of the elderly people. The drugs currently approved for the treatment of AD can only reduce the symptoms severity of AD, but can't cure AD or prevent the deterioration of AD. Over the past 40 years, there have been numerous treatments for AD, including compounds that prevent amyloid deposition in the brain or remove existing amyloid plaques, but their clinical curative effects are not significant. Therefore, more basic and clinical studies are needed to improve our understanding of the biological mechanism of AD. Experimental animal models are very important not only for the study of the pathogenesis of AD, but also for the development of AD drugs. This paper reviewed the main histopathological characteristics, genetic factors, the current animal models and model evaluation of AD.

Key words: Alzheimer's disease, Animal models, Histopathological characteristics, Amyloid, Evaluation

CLC Number:

R-332

Zhejin SHENG, Limei LI. Research Progress in Animal Model of Alzheimer's Disease[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 342-350.

Figures/Tables 4

References 51

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模型名称 Name of model	基因/小鼠类型 Type of gene/mouse	神经病理学特征 Characteristics of neuoropathology	行为/认知障碍 Behavioral / cognitive disorder
PDAPP	APP^*	海马、大脑皮层胶质增生（3～4月龄），营养不良性神经突，海马的突触和树突减少	物体识别，空间记忆受损（3月龄），暗示条件恐惧反射受损（11月龄）
APP V717I	APP^*	Aβ斑块（10月龄），脑血管内淀粉样蛋白沉积（15月龄），淀粉样蛋白相关炎症，营养不良性神经突，过度磷酸化的Tau蛋白，无NFTs	空间和非空间定向及记忆障碍（6月龄），焦虑/不安情绪加重（2月龄），多动症和攻击性
G2576	APP^*	Aβ斑块（6～9月龄），氧化脂质损伤、星形胶质细胞增生和小胶质细胞增生（11～13月龄）	空间学习、工作记忆和条件化情景恐惧受损（6月龄），认知功能进行性损伤（12月龄）
APP23	APP^*	Aβ斑块（6月龄），过度磷酸化Tau，无NFTs，营养不良性神经突，海马CA1区神经元丢失，CAA	空间记忆缺陷（3月龄），被动回避的记忆缺陷（25月龄）
J20 (PDGF-APPSw, Ind)	APP^*	Aβ斑块，营养不良性神经突，无NFTs，细胞减少丢失，突触的标志物减少，补体免疫反应增加	学习和记忆障碍（4月龄），多动，记忆缺陷（6月龄）
5×FAD	APP^, PSEN1^	Aβ斑块（2月龄），胶质增生和突触变性，大脑皮层V区神经元丢失	记忆和暗示与关联条件恐惧受损（6月龄）
APP (V717I) ×PS1 (A246E)	APP^&, PSEN1^*	可溶性Aβ寡聚物（2月龄），Aβ斑块（6～9月龄），淀粉样蛋白相关炎症，CAA（8月龄），异常磷酸化Tau蛋白，营养不良性神经突，但无NFTs	空间和非空间定向及记忆障碍（5月龄），联想学习障碍、多动症、焦虑和攻击性
APPswe/PSEN1dE9 (line 85)	APP^, PSEN1^	Aβ斑块（6月龄），神经元中度丢失（8～10月龄），无NFTs，突触标志物减少和补体免疫反应性增加	认知和情境记忆障碍（6月龄），空间学习障碍（12月龄），筑巢、挖洞等自发行为改变
Tg2576/Tau(P301L) (APPSwe-Tau)	APP^, MAPT^	Aβ斑块整个皮质、海马体和杏仁核（9月龄），星形细胞和小胶质细胞增多，CAA和NFTs（9～11月龄）	运动障碍（4～6月龄）
PLB1-triple (hAPP/hTau/hPS1)	APP^&, MAPT^&, PSEN1^&	Aβ寡聚体，海马和皮质过度磷酸化Tau蛋白（6月龄），无明显NFTs，脑皮层代谢低下，基底前脑和腹中脑代谢活性增加	认知记忆和空间学习缺陷（5月龄），海马的结构可塑性受损
3×Tg	APP^, PSEN1^, MAPT^*	Aβ斑块（6月龄），NFTs（12月龄），突触功能障碍，突触可塑性缺陷	记忆缺陷，暗示与关联条件恐惧受损（4～5月龄）
hTau	mMAPT^#, hMAPT^*	NFTs（6月龄），NFTs和神经元丢失（15月龄）	工作记忆和空间记忆的缺陷（12月龄）
rTg (TauP301L) 4510	MAPT^*	无NFTs和神经元丢失（4～6月龄）	空间记忆减退和新物体识别障碍（1.5～4月龄），暗示与关联条件恐惧受损
APOE4 Knock-In^§	APOE^$	大脑及血清中APOE水平显著高；禁食6 h后，血清胆固醇和三酰甘油升高	无数据
PS1^£	PSEN1^*	无严重的神经病理学异常（24月龄）	记忆未受影响（24月龄）

模型名称 Name of model	基因/小鼠类型 Type of gene/mouse	神经病理学特征 Characteristics of neuoropathology	行为/认知障碍 Behavioral / cognitive disorder
PDAPP	APP^*	海马、大脑皮层胶质增生（3～4月龄），营养不良性神经突，海马的突触和树突减少	物体识别，空间记忆受损（3月龄），暗示条件恐惧反射受损（11月龄）
APP V717I	APP^*	Aβ斑块（10月龄），脑血管内淀粉样蛋白沉积（15月龄），淀粉样蛋白相关炎症，营养不良性神经突，过度磷酸化的Tau蛋白，无NFTs	空间和非空间定向及记忆障碍（6月龄），焦虑/不安情绪加重（2月龄），多动症和攻击性
G2576	APP^*	Aβ斑块（6～9月龄），氧化脂质损伤、星形胶质细胞增生和小胶质细胞增生（11～13月龄）	空间学习、工作记忆和条件化情景恐惧受损（6月龄），认知功能进行性损伤（12月龄）
APP23	APP^*	Aβ斑块（6月龄），过度磷酸化Tau，无NFTs，营养不良性神经突，海马CA1区神经元丢失，CAA	空间记忆缺陷（3月龄），被动回避的记忆缺陷（25月龄）
J20 (PDGF-APPSw, Ind)	APP^*	Aβ斑块，营养不良性神经突，无NFTs，细胞减少丢失，突触的标志物减少，补体免疫反应增加	学习和记忆障碍（4月龄），多动，记忆缺陷（6月龄）
5×FAD	APP^, PSEN1^	Aβ斑块（2月龄），胶质增生和突触变性，大脑皮层V区神经元丢失	记忆和暗示与关联条件恐惧受损（6月龄）
APP (V717I) ×PS1 (A246E)	APP^&, PSEN1^*	可溶性Aβ寡聚物（2月龄），Aβ斑块（6～9月龄），淀粉样蛋白相关炎症，CAA（8月龄），异常磷酸化Tau蛋白，营养不良性神经突，但无NFTs	空间和非空间定向及记忆障碍（5月龄），联想学习障碍、多动症、焦虑和攻击性
APPswe/PSEN1dE9 (line 85)	APP^, PSEN1^	Aβ斑块（6月龄），神经元中度丢失（8～10月龄），无NFTs，突触标志物减少和补体免疫反应性增加	认知和情境记忆障碍（6月龄），空间学习障碍（12月龄），筑巢、挖洞等自发行为改变
Tg2576/Tau(P301L) (APPSwe-Tau)	APP^, MAPT^	Aβ斑块整个皮质、海马体和杏仁核（9月龄），星形细胞和小胶质细胞增多，CAA和NFTs（9～11月龄）	运动障碍（4～6月龄）
PLB1-triple (hAPP/hTau/hPS1)	APP^&, MAPT^&, PSEN1^&	Aβ寡聚体，海马和皮质过度磷酸化Tau蛋白（6月龄），无明显NFTs，脑皮层代谢低下，基底前脑和腹中脑代谢活性增加	认知记忆和空间学习缺陷（5月龄），海马的结构可塑性受损
3×Tg	APP^, PSEN1^, MAPT^*	Aβ斑块（6月龄），NFTs（12月龄），突触功能障碍，突触可塑性缺陷	记忆缺陷，暗示与关联条件恐惧受损（4～5月龄）
hTau	mMAPT^#, hMAPT^*	NFTs（6月龄），NFTs和神经元丢失（15月龄）	工作记忆和空间记忆的缺陷（12月龄）
rTg (TauP301L) 4510	MAPT^*	无NFTs和神经元丢失（4～6月龄）	空间记忆减退和新物体识别障碍（1.5～4月龄），暗示与关联条件恐惧受损
APOE4 Knock-In^§	APOE^$	大脑及血清中APOE水平显著高；禁食6 h后，血清胆固醇和三酰甘油升高	无数据
PS1^£	PSEN1^*	无严重的神经病理学异常（24月龄）	记忆未受影响（24月龄）

造模方式Modeling method	表型Phenotype
脑室内注射β-淀粉样蛋白	急性或慢性脑室内注射或海马内注射Aβ40、β42或FAB（亚铁淀粉样丁硫氨酸）引起学习和认知障碍
雌性大鼠去卵巢后海马区注射β-淀粉样蛋白片段25-35	短记忆和空间记忆功能恶化，皮质醇水平升高，并伴有葡萄糖、脂质和骨代谢异常，空腹胰岛素抵抗
脑室内注射链脲佐菌素	与AD相似的进行性记忆丧失
脑室内注射软海绵酸	脑室内注射软海绵酸14 d导致p-Tau和Aβ的增加，造成认知障碍
脑室内注射AF64A	胆碱毒素选择性地降低乙酰胆碱、乙酰胆碱酯酶、胆碱乙酰转移酶、乙酰胆碱酯酶、钾离子水平，并可减少哇巴因刺激的乙酰胆碱酯酶释放水平
侧脑室注射192-IgG-saporin	免疫毒素造成持续性损伤，造成胆碱能通路受损，出现认知障碍
鹅膏蕈氨酸和其他兴奋性毒素（NMDA、喹啉酸、红藻氨酸和奎司喹酸）	单独使用兴奋性毒素或与Aβ联用可引起海马胆碱能神经元丢失，出现认知功能障碍
腹腔注射东莨菪碱	学习障碍
缺氧/中风	记忆障碍，血管性痴呆

造模方式Modeling method	表型Phenotype
脑室内注射β-淀粉样蛋白	急性或慢性脑室内注射或海马内注射Aβ40、β42或FAB（亚铁淀粉样丁硫氨酸）引起学习和认知障碍
雌性大鼠去卵巢后海马区注射β-淀粉样蛋白片段25-35	短记忆和空间记忆功能恶化，皮质醇水平升高，并伴有葡萄糖、脂质和骨代谢异常，空腹胰岛素抵抗
脑室内注射链脲佐菌素	与AD相似的进行性记忆丧失
脑室内注射软海绵酸	脑室内注射软海绵酸14 d导致p-Tau和Aβ的增加，造成认知障碍
脑室内注射AF64A	胆碱毒素选择性地降低乙酰胆碱、乙酰胆碱酯酶、胆碱乙酰转移酶、乙酰胆碱酯酶、钾离子水平，并可减少哇巴因刺激的乙酰胆碱酯酶释放水平
侧脑室注射192-IgG-saporin	免疫毒素造成持续性损伤，造成胆碱能通路受损，出现认知障碍
鹅膏蕈氨酸和其他兴奋性毒素（NMDA、喹啉酸、红藻氨酸和奎司喹酸）	单独使用兴奋性毒素或与Aβ联用可引起海马胆碱能神经元丢失，出现认知功能障碍
腹腔注射东莨菪碱	学习障碍
缺氧/中风	记忆障碍，血管性痴呆

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