Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer’s disease

• DOI: 10.1016/j.neuron.2024.12.025
• Publication Date: 2025-01-20T15:33:51Z
• Authors: Andrew Octavian S...; Erinne Cherisse Ong; Taisiia Nazarenko; Shuying Mao; Lina Komarek; Maik Thalmann; Veronika Hantakova; Lena Spieth; Stefan A. Berghoff; Helena J. Barr; Maximilian Hingerl; Friederike Börensen; Johannes Hirrlinger; Mikael Simons; Beth Stevens; Constanze Depp; Klaus-Armin Nave
• Keywords: Male; genetics [Plaque, Amyloid]; metabolism [Amyloid beta-Peptides]; genetics [Alzheimer Disease]; Mice, Transgenic; amyloid-β; pathology [Alzheimer Disease]; Mice; Amyloid beta-Protein Precursor; Animals; Humans; ddc:610; pathology [Plaque, Amyloid]; Transgenes; Amyloid beta-Peptides; amyloid plaque; 5xFAD; metabolism [Plaque, Amyloid]; transgenic mouse; Disease Models, Animal; genetics [Amyloid beta-Protein Precursor]; Thy1 promoter; Female; Alzheimer’s disease; light-sheet microscopy; metabolism [Alzheimer Disease]

In Alzheimer's disease (AD) research, the 5xFAD mouse model is commonly used as a heterozygote crossed with other genetic models to study AD pathology. We investigated whether the parental origin of the 5xFAD transgene affects plaque deposition. Using quantitative light-sheet microscopy, we found that paternal inheritance of the transgene led to a 2-fold higher plaque burden compared with maternal inheritance, a finding consistent across multiple 5xFAD colonies. This effect was not due to gestation in or rearing by 5xFAD females. Immunoblotting suggested that transgenic inheritance modulates transgenic protein expression, potentially due to genomic imprinting of the Thy1.2 promoter. Surprisingly, fewer than 20% of 5xFAD studies report breeding schemes, suggesting that this factor might confound previous findings. Our data highlight a significant determinant of plaque burden in 5xFAD mice and underscore the importance of reporting the parental origin of the transgene to improve scientific rigor and reproducibility in AD research.