Authors: Gulbranson, Daniel R.; Ho, Kaitlyn; Yu, Gui-Qiu; Yu, Xinxing; Das, Melanie; Shao, Eric; Kim, Daniel; Zhang, Weiping J.; Choudhary, Krishna; Thomas, Reuben; Mucke, Lennart
Issue: eNeuro . 2021 May 13;8(3):ENEURO.0089-21.2021.
Diverse gene products contribute to the pathogenesis of Alzheimer’s disease (AD). Experimental models have helped elucidate their mechanisms and impact on brain functions. Human amyloid precursor protein (hAPP) transgenic mice from line J20 (hAPP-J20 mice) are widely used to simulate key aspects of AD. However, they also carry an insertional mutation in noncoding sequence of one Zbtb20 allele, a gene involved in neural development. We demonstrate that heterozygous hAPP-J20 mice have reduced Zbtb20 expression in some AD-relevant brain regions, but not others, and that Zbtb20 levels are higher in hAPP-J20 mice than heterozygous Zbtb20 knockout (Zbtb20+/–) mice. Whereas hAPP-J20 mice have premature mortality, severe deficits in learning and memory, other behavioral alterations, and prominent nonconvulsive epileptiform activity, Zbtb20+/– mice do not. Thus, the insertional mutation in hAPP-J20 mice does not ablate the affected Zbtb20 allele and is unlikely to account for the AD-like phenotype of this model. Significance Statement Genetically modified mice can help unravel complex disorders such as Alzheimer’s disease (AD) by revealing effects of pathogenic drivers on neural networks and behaviors. Inadvertent genome modifications can occur during the generation of such models but their consequences are rarely explored in depth, even though they could confound the interpretation of phenotypes and therapeutic interventions. hAPP-J20 mice simulate multiple aspects of AD but also carry an insertional mutation in one Zbtb20 allele. Our study differentiates specific from nonspecific Zbtb20 antibodies and provides evidence that the functional AD-like alterations of hAPP-J20 mice are not caused by hypofunction of Zbtb20. We further demonstrate in Zbtb20+/– mice that neural development and brain functions are well preserved when Zbtb20 levels are reduced in half.