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Aging and disease    2020, Vol. 11 Issue (5) : 1235-1259     DOI: 10.14336/AD.2019.1026
Review Article |
Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications
Chi Him Poon1, Yingyi Wang1, Man-Lung Fung1, Chengfei Zhang2, Lee Wei Lim1,*
1School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
2Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide and causes severe financial and social burdens. Despite much research on the pathogenesis of AD, the neuropathological mechanisms remain obscure and current treatments have proven ineffective. In the past decades, transgenic rodent models have been used to try to unravel this disease, which is crucial for early diagnosis and the assessment of disease-modifying compounds. In this review, we focus on transgenic rodent models used to study amyloid-beta pathology in AD. We also discuss their possible use as promising tools for AD research. There is still no effective treatment for AD and the development of potent therapeutics are urgently needed. Many molecular pathways are susceptible to AD, ranging from neuroinflammation, immune response, and neuroplasticity to neurotrophic factors. Studying these pathways may shed light on AD pathophysiology as well as provide potential targets for the development of more effective treatments. This review discusses the advantages and limitations of these models and their potential therapeutic implications for AD.

Keywords Alzheimer’s disease      amyloid-beta      neuroinflammation      neuroplasticity      neurotrophic factors     
Corresponding Authors: Lim Lee Wei   
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These authors contributed equally to this work.

Just Accepted Date: 31 March 2020   Issue Date: 21 September 2020
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Poon Chi Him
Wang Yingyi
Fung Man-Lung
Zhang Chengfei
Lim Lee Wei
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Poon Chi Him,Wang Yingyi,Fung Man-Lung, et al. Rodent Models of Amyloid-Beta Feature of Alzheimer’s Disease: Development and Potential Treatment Implications[J]. Aging and disease, 2020, 11(5): 1235-1259.
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Figure 1.  Timeline illustrating the development of transgenic mouse and rat models of AD.
Animal modelModel backgroundTransgeneAmyloid pathologyOther pathologyBehavioral testRef.
Tg2576C57BL/6Human APP695 (Swedish)Aβ plaques at 10-12 months,oligomeric Aβ generationSynaptic loss at 15-18 months.Behavioral impairment in novel object recognition at 12-15 months, Morris water maze at 6 months and Y maze at 10 months.[55, 123, 237]
TgAPP23C57BL/6JHuman APP751 (Swedish)Aβ plaques at 6 monthsIncreased level of phospho-tau at 6 months, phospho-tau deposition surrounding plaques at 12 months, neuronal loss in area of CA1 at 14-18 months.Behavioral impairment in novel object recognition at 3-4 months, Morris water maze at 3 months.[56, 238, 239]
PDAPPSwiss Webster × B6D2F1Human APP (Indiana)Aβ plaques at 6-9 monthsSynaptic loss.Behavioral impairment in novel object recognition at 6 months, Morris water maze at 3 months.[54, 240]
J20C57BL/6 × DBA/2 F2Human APP (Swedish and Indiana)Diffuse amyloid deposits at 5-6 months and larger neuritic plaques at 9 monthsPhospho-neurofilaments.Behavioral impairment in novel object recognition at 4 months, Morris water maze at 6-9 months.[53, 68, 241, 242]
TgCRND8C3H/He × C57BL/6Human APP695 (Swedish and Indiana)Aβ plaques at 3 months,dense core plaques at 5 months, spreading to the cerebellum and brainstem by 8-9 monthsAstrocytic gliosis and microglial activation in regions around plaques.Behavioral impairment in novel object recognition at 3-5 months, Morris water maze at 3 months.[67, 69, 243]
AppNL-FC57BL/6Human APP (Swedish and Iberian)Aβ plaque at 6 monthsSynaptic loss, microgliosis and astrocytosisBehavioral impairment in Y-maze at 18 months, no impairment in Morris water maze at 18 months[76]
5XFADTg6799×Tg7031 ×Tg7092Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)Intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition, gliosis, at 2 monthsSignificant neurodegeneration and neuronal loss.Behavioral impairment in Y-maze at 4-5 months, decreased Interest in social-related behaviors at 3-12 months. Morris water maze at 4 months.[81, 244, 245]
APP23 x PS1-R278IC57BL/6JHuman APP23 (Swedish K651N, M652L); Human PS1 (R278I)Aβ plaque at 6 monthsAstrocytosis.Behavioral impairment in Y-maze at 3-4 months; no significant impairment in Morris water maze[82]
Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)less cortical amyloid plaque at 7 months compared to 5XFAD miceEnhanced process ramification and phagocytic marker expression in plaque-associated microglia; improved dystrophic neurites.No cognitive impairment in contextual fear conditioning test.[85]
3xTg-ADC57BL6/129SvJHuman APP (Swedish); Human PS1 (M146V); Human Tau (P301L)Aβ plaque at 6 monthssynaptic dysfunction and increased microglia activation at 6 months; Tau alteration at 12-15 monthsRetention deficits in Morris water maze and contextual fear memory[87-89]
Table 1  Mouse models of amyloid-beta pathology in Alzheimer’s disease.
Animal modelModel backgroundTransgeneAmyloid pathologyOther pathologyBehavioral testRef.
Tg2576C57BL/6Human APP695 (Swedish)Aβ plaques at 10-12 months,oligomeric Aβ generationSynaptic loss at 15-18 months.Behavioral impairment in novel object recognition at 12-15 months, Morris water maze at 6 months and Y maze at 10 months.[55, 123, 237]
TgAPP23C57BL/6JHuman APP751 (Swedish)Aβ plaques at 6 monthsIncreased level of phospho-tau at 6 months, phospho-tau deposition surrounding plaques at 12 months, neuronal loss in area of CA1 at 14-18 months.Behavioral impairment in novel object recognition at 3-4 months, Morris water maze at 3 months.[56, 238, 239]
PDAPPSwiss Webster × B6D2F1Human APP (Indiana)Aβ plaques at 6-9 monthsSynaptic loss.Behavioral impairment in novel object recognition at 6 months, Morris water maze at 3 months.[54, 240]
J20C57BL/6 × DBA/2 F2Human APP (Swedish and Indiana)Diffuse amyloid deposits at 5-6 months and larger neuritic plaques at 9 monthsPhospho-neurofilaments.Behavioral impairment in novel object recognition at 4 months, Morris water maze at 6-9 months.[53, 68, 241, 242]
TgCRND8C3H/He × C57BL/6Human APP695 (Swedish and Indiana)Aβ plaques at 3 months,dense core plaques at 5 months, spreading to the cerebellum and brainstem by 8-9 monthsAstrocytic gliosis and microglial activation in regions around plaques.Behavioral impairment in novel object recognition at 3-5 months, Morris water maze at 3 months.[67, 69, 243]
AppNL-FC57BL/6Human APP (Swedish and Iberian)Aβ plaque at 6 monthsSynaptic loss, microgliosis and astrocytosisBehavioral impairment in Y-maze at 18 months, no impairment in Morris water maze at 18 months[76]
5XFADTg6799×Tg7031 ×Tg7092Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)Intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition, gliosis, at 2 monthsSignificant neurodegeneration and neuronal loss.Behavioral impairment in Y-maze at 4-5 months, decreased Interest in social-related behaviors at 3-12 months. Morris water maze at 4 months.[81, 244, 245]
APP23 x PS1-R278IC57BL/6JHuman APP23 (Swedish K651N, M652L); Human PS1 (R278I)Aβ plaque at 6 monthsAstrocytosis.Behavioral impairment in Y-maze at 3-4 months; no significant impairment in Morris water maze[82]
Human APP (Swedish, Florida, London); Human PS1 (M146L, L286V)less cortical amyloid plaque at 7 months compared to 5XFAD miceEnhanced process ramification and phagocytic marker expression in plaque-associated microglia; improved dystrophic neurites.No cognitive impairment in contextual fear conditioning test.[85]
3xTg-ADC57BL6/129SvJHuman APP (Swedish); Human PS1 (M146V); Human Tau (P301L)Aβ plaque at 6 monthssynaptic dysfunction and increased microglia activation at 6 months; Tau alteration at 12-15 monthsRetention deficits in Morris water maze and contextual fear memory[87-89]
Table 2  Rat models of amyloid-beta pathology in Alzheimer’s disease.
Figure 2.  Human APP695 and APP751 are essential genes involved in the generation of transgenic rodent models of Alzheimer’s disease (AD). Swedish (red), Iberian / Florida (Black) and Indiana / London (Green) are the major mutations introduced into the human APP in rodents to induce rapid amyloid plaque formation. One of the rodent models that encompass numerous mutations is 5XFAD, 3 mutations of which are located on human APP751. Representative photomicrographs showing intense amyloid plaque formation in various brain regions demonstrate severe Aβ pathology in 5XFAD mouse model in the age of 6 months. These images highlight the Aβ pathological progression in brain regions established for memory processes.
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