Autophagy Impairment in App Knock-in Alzheimer's Model Mice

Alzheimer's disease (AD) is characterized by impaired protein homeostasis leading to amyloid-beta peptide (A beta) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust A beta pathology, providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains from two different types of App knock-in mice, App(NL-F) and App(NL-G-F) mice, exhibiting AD-like pathology. In AD postmortem brains, p62 levels are increased and p62-positive staining is detected in neurons, including potential axonal beadings, as well as in the vasculature and in corpora amylacea. Interestingly, p62 is also increased in the neurons in 12-month-old App(NL-G-F) mice. In brain homogenates from 12-month-old App(NL-G-F) mice, both p62 and light chain 3 (LC3)-II levels are increased as compared to wildtype (WT) mice, indicating inhibited autophagy. Double immunostaining for LC3 and A beta revealed LC3-positive puncta in hippocampus of 24-month-old App(NL-F) mice around the A beta plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the A beta plaques. Taken together, autophagy is impaired in App knock-in mice upon increased A beta pathology, indicating that App knock-in mouse models provide a platform for understanding the correlation between A beta and autophagy.