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Evaluation of Animal Models by Comparison with Human Late-Onset Alzheimer's Disease
Bu-Yeo Kim1, Hye-Sun Lim2, Yoonju Kim2
1Herbal Medicine Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea. buykim@kiom.re.kr.
Abstract:
Despite many efforts to alleviate the pathological conditions of Alzheimer's disease (AD), effective therapeutic drugs have not been developed, mainly because of the lack of molecular information about AD and animal models. We observed the reciprocal regulation of AD-associated genes (AD genes) and their related functions. Upregulated AD genes were positioned in central regions in the protein-protein interaction network and were involved in inflammation and DNA repair pathways. Downregulated AD genes positioned in the periphery of the network were associated with metabolic pathways. Using these features of AD genes, we found that 5×FAD, amyloid β-injected mice, and rats in the initial phases after bilateral common carotid artery occlusion (BCCAO) exhibited patterns that were most similar to those of AD. In contrast, using differentially expressed genes from animal models, we observed that 3×Tg and animals in late phases of BCCAO were positioned close to AD genes.
Insights
Researchers identified key Alzheimer's disease (AD) gene patterns. Certain animal models, like 5×FAD mice, closely mimic AD's molecular profile, aiding future therapeutic development.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Developing effective Alzheimer's disease (AD) therapeutics remains challenging due to incomplete molecular understanding and limitations of current animal models.
- Alzheimer's disease is characterized by complex genetic and functional dysregulation.
- Identifying reliable animal models that accurately reflect human AD pathology is crucial for drug discovery.
Purpose of the Study:
- To investigate the reciprocal regulation of AD-associated genes and their functional pathways.
- To identify and characterize animal models that best recapitulate the molecular features of Alzheimer's disease.
- To establish a framework for evaluating the suitability of animal models for AD research.
Main Methods:
- Analysis of protein-protein interaction networks for AD-associated genes.
- Characterization of gene expression patterns in various AD models, including 5×FAD mice, amyloid β-injected mice, and rats undergoing bilateral common carotid artery occlusion (BCCAO) at different phases.
- Comparison of gene expression profiles between human AD and animal models.
Main Results:
- Upregulated AD genes are centrally located in protein-protein interaction networks, primarily associated with inflammation and DNA repair.
- Downregulated AD genes are peripherally located and linked to metabolic pathways.
- Initial phases of 5×FAD mice, amyloid β-injected mice, and BCCAO rats showed molecular patterns most similar to human AD.
- 3×Tg mice and late-phase BCCAO rats exhibited gene expression patterns distinct from human AD.
Conclusions:
- Specific animal models, particularly in their early stages, can effectively mirror the molecular pathology of Alzheimer's disease.
- Understanding the network topology and pathway associations of AD genes is key to selecting appropriate disease models.
- This study provides a basis for selecting more accurate animal models for Alzheimer's disease research and therapeutic development.