The establishment and application of animal models for neurodegenerative diseases

The increasing prevalence of neurodegenerative diseases constitutes a significant challenge to public health systems globally. Consequently, the quest for efficacious preventive and therapeutic strategies has assumed center stage in public health discourse. Animal models serve as indispensable instruments in neurodegenerative disease research, offering foundational data that inform our understanding of the pathological mechanisms and contribute to the development of novel therapeutic paradigms. This manuscript delineates the methodologies for constructing animal models germane to prevalent neurodegenerative conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. The establishment of these models incorporates factors like genetic etiology, pathological signatures, and the temporal course of disease progression. Traditional techniques in model development frequently exhibit shortcomings in disease specificity, phenotypic stability, and alignment with the pathological evolution of human ailments. However, advancements in gene-editing technologies, notably CRISPR/Cas9, facilitate the emulation of human neurodegenerative disease pathologies with increased precision. This augments the relevance of animal models as instrumental tools in pharmaceutical development and the formulation of disease prevention strategies. In addition to conventional neurodegenerative animal models, the manuscript explores advancements in innovative models including chemical induction models, human brain tissue transplantation models, spontaneous models, and accelerated aging models. A focal point of the discourse is the transformative impact of gene-editing technologies on animal model development, with emphasis on the theoretical foundations and methodologies for creating polygenic breeding models and genetically diverse, gene-edited models. 1. Key gene-editing technologies applied in the domain of animal model creation encompass gene knock-in/knock-out, RNA interference (RNAi), and CRISPR/Cas9. Gene knock-in entails the integration of a target gene into a predetermined genomic location, while gene knock-out involves the excision of a specific gene, either entirely or partially. Both processes are predicated on homologous recombination, leveraging the innate capability of DNA molecules for homologous pairing and exchange to insert the target gene at precise chromosomal loci. 2. Complex human diseases frequently involve an array of genes or quantitative trait loci (QTL), each exerting a modest impact on the disease phenotype. When multiple QTLs are inherited, disease manifestation or predisposition may ensue. The advancement of mouse models for Alzheimer’s Disease epitomizes this intricate multi-gene or multi-locus modification process. As stronger genetic drivers and their combinations are identified, the selection and arrangement of divergent mouse strains can refine these models further. 3. The utility of genetically diverse gene-edited animal models lies in their ability to replicate human genetic variability by exploiting the phenotypic differences inherent in mice with assorted genetic backgrounds. The integration of gene-edited animal models into neurodegenerative disease research enhances our mechanistic understanding of these conditions. The manuscript elucidates emergent research avenues in gene-edited animal models, including the capabilities of polygenic models to emulate intricate disease states and the evolving role of comorbidity models. These tools are pivotal for a comprehensive understanding of disease pathogenesis, the elucidation of environmental and genetic interactions, the screening of pharmaceutical candidates, and the conception of innovative therapeutic interventions. Although existing models fail to capture the full complexity of human diseases, there is a rational expectation that ongoing technological innovations will ameliorate these limitations, thereby influencing the future trajectory of neurodegenerative disease research.