Imagine your brain is a bustling city and the proteins it produces are like the citizens. In Alzheimer’s disease, these citizens start to clutter up the streets, causing chaos and dysfunction. But have no fear, scientists are investigating ways to clean up this mess! A recent study focused on a specific type of mouse, called App knock-in mice, which mimic Alzheimer’s pathology. By studying these mice, researchers found that a process called autophagy, which is like a garbage disposal system for cells, was impaired. Specifically, they discovered that a protein called p62, known for slurping up trash in cells, was increased in both Alzheimer’s postmortem brains and older App knock-in mice. This suggests that the accumulation of amyloid-β peptide (Aβ), a hallmark of Alzheimer’s, may interfere with autophagy. The researchers even spotted pockets of trash-filled vesicles called autophagic vacuoles surrounding Aβ plaques in brain images! This exciting research provides valuable insights into the relationship between Aβ and autophagy, and brings us closer to finding ways to unknot the protein tangles in the brain. If you’re eager to learn more about this fascinating study, check out the full article!

Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ 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, AppNL–F and AppNL–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 AppNL–G–F mice. In brain homogenates from 12-month-old AppNL–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 Aβ revealed LC3-positive puncta in hippocampus of 24-month-old AppNL–F mice around the Aβ plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the Aβ plaques. Taken together, autophagy is impaired in App knock-in mice upon increased Aβ pathology, indicating that App knock-in mouse models provide a platform for understanding the correlation between Aβ and autophagy.

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