Inhibitory Network Alterations in Knock-In Models of Alzheimer's Disease
Altered inhibitory networks have become an established phenotype in transgenic mouse models of Alzheimer’s disease (AD) which overexpress mutant human amyloid precursor protein (APP). One of the most prominent characterizations of these network changes is the ectopic expression of neuropeptide-y (NPY) in the mossy fibers of the hippocampus. Recently, the limitations of these transgenic mouse models, such as APP overexpression and the role of non-amyloid-beta metabolites, have become more apparent and the need to determine which observed phenotypes are not a result of confounding factors has become essential to understand their translational potential. To determine whether this ectopic hippocampal NPY expression constitutes an artifact of transgenic lines, we used two knock-in models of the disease, the AppNL and AppNL-F lines, harboring one and two mutations in APP, respectively. We found no changes in the levels of mossy fiber NPY expression in AppNL mice and reduced NPY immunoreactivity in AppNL-F animals compared to control mice. These data thus suggest that the observed ectopic NPY expression in transgenic lines could result from APP overexpression. This study highlights the important task the field will need to undertake in understanding what phenotypes in transgenic models are artifacts as studies move towards knock-in lines to study AD.