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ARS Home » Midwest Area » Columbia, Missouri » Plant Genetics Research » Research » Publications at this Location » Publication #410179
Research Project: Validate Causative Mutations in Agriculturally-Important Vertebrates

Location: Plant Genetics Research

Title: Impaired skeletal development by disruption of presenilin-1 in pigs and generation of novel pig models for Alzheimer’s disease

Author
item UH, KYUNGJUN - Korea Research Institute Of Bioscience And Biotechnology
item MONARCH, KAYLYNN - University Of Missouri
item REESE, EMILY - University Of Missouri
item RODRIGUEZ, KATHERINE - University Of Missouri
item YOON, JUNCHUL - University Of Missouri
item SPATE, LEE - University Of Missouri
item SAMUEL, MELISSA - University Of Missouri
item KOH, SEHWON - University Of Missouri
item Chen, Paula
item JAROME, TIMOTHY - Virginia Polytechnic Institution & State University
item ALLEN, TIMOTHY - Florida International University
item PRATHER, RANDALL - University Of Missouri
item LEE, KIHO - University Of Missouri

Submitted to: Journal of Alzheimer's Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/27/2024
Publication Date: 9/10/2024
Citation: Uh, K., Monarch, K., Reese, E.D., Rodriguez, K., Yoon, J.D., Spate, L.D., Samuel, M.S., Koh, S., Chen, P.R., Jarome, T., Allen, T., Prather, R.S., Lee, K. 2024. Impaired skeletal development by disruption of presenilin-1 in pigs and generation of novel pig models for Alzheimer’s disease. Journal of Alzheimer's Disease. 101(2):445-461. https://doi.org/10.3233/JAD-231297.
DOI: https://doi.org/10.3233/JAD-231297

Interpretive Summary: Several genes have been linked to early onset of Alzheimer’s disease with one of them being presenilin 1 (PSEN1). The role of PSEN1 was investigated in pigs which have been shown to be suitable models of disease in humans. After introducing mutations in PSEN1, pigs were born but died shortly after birth due to severe skeletal system defects that primarily impacted the spine. Additionally, pigs lacking function PSEN1 had abnormal distribution of different cell populations within the brain that could be linked to the development of neurodegenerative disorders, such as Alzheimer's disease. These pigs will serve as a novel resource to study pathogenesis of different diseases.

Technical Abstract: Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer’s disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (exon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (exon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one exon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1E9/+ pigs to study their relevance to clinical Alzheimer’s diseases.